Losartan liquid formulations and methods of use

ABSTRACT

The present disclosure relates to stable, liquid pharmaceutical compositions of losartan or pharmaceutically acceptable salts thereof for oral administration. The present disclosure further provides powder compositions for reconstitution to provide a liquid formulation. In further aspects, the present disclosure relates to processes for preparation of such pharmaceutical compositions, and methods of treating a subject in need of losartan by administration of a formulation described herein.

TECHNICAL FIELD

The present disclosure relates to stable, liquid pharmaceuticalcompositions of losartan or pharmaceutically acceptable salts thereoffor oral administration. The present disclosure further provides powdercompositions for reconstitution to provide a liquid formulation. Infurther aspects, the present disclosure relates to processes forpreparation of such pharmaceutical compositions, and methods of treatinga subject in need of losartan by administration of a formulationdescribed herein.

BACKGROUND

Hypertension is a serious medical condition wherein the blood pressureof a subject is elevated, increasing the risk of damage to varioustissues and organs, including the heart, brain, and kidneys. Accordingto a World Health Organization estimate, as of 2019, 1.13 billion peopleworldwide experience hypertension.

Losartan is an angiotensin II receptor blocker marketed under the tradename COZAAR®, which is indicated: (1) to lower blood pressure in adultsand children greater than 6 years old; (2) to reduce the risk of strokein patients with hypertension and left ventricular hypertrophy; and (3)to treat diabetic nephropathy with an elevated serum creatinine andproteinuria in patients with type 2 diabetes and a history ofhypertension.

COZAAR® is available as 25 mg, 50 mg and 100 mg film coated tablets. Amajor problem associated with the tablet dosage form is the difficultyin oral administration for patients with swallowing difficulties, e.g.,geriatric patients, pediatric patients, patients with neurologicaldisorders, and patients with oral and esophageal cancers. Additionally,patients with underlying disease conditions may experience lowerbioavailability from solid dosage forms of losartan.

The prescribing information supplied with COZAAR® describes thepreparation of a losartan suspension by dispersing COZAAR® tablets witha suspending agent and a sweetener. This is the only commerciallyavailable liquid losartan preparation. However, these compoundedpreparations can be stored only up to 4 weeks under refrigeratedconditions. Additionally, compounded preparations may not bebioequivalent to COZAAR® tablets, which may affect the therapeuticefficacy of such preparations.

Therefore, there remains a need for a stable, liquid pharmaceuticalcomposition of losartan that is safely administrable and bioequivalentto COZAAR® tablets.

BRIEF SUMMARY Pharmaceutical Composition

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising losartan or a pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable excipients, whereinthe pharmaceutical composition is suitable for oral administration,liquid, substantially free of impurities, and stable for at least 12months. In some aspects, the pharmaceutical composition is bioequivalentto COZAAR®. In some aspects, the pharmaceutical composition is notbioequivalent to COZAAR®.

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising losartan or a pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable excipients, whereinthe pharmaceutical composition is suitable for oral administration,liquid, bioequivalent to COZAAR®, substantially free of impurities, andstable for at least 12 months.

Forms of Losartan

In some aspects, the pharmaceutical composition comprises losartan.

In some aspects, the pharmaceutical composition comprises apharmaceutically acceptable salt of losartan. In some aspects, thepharmaceutical composition comprises losartan potassium.

Excipients

In some aspects, the pharmaceutical composition comprises two or morepharmaceutically acceptable excipients selected from the groupconsisting of: a suspending agent, a pH modifying agent, an emulsifyingagent, an antioxidant, a chelating agent, a preservative, an antifoamingagent, a solubilizer, a vehicle, a surfactant or wetting agent, asweetener, a stabilizer, a flavoring agent, and a colorant.

In some aspects, the pharmaceutical composition comprises acrystallization inhibitor or a crystal growth inhibitor. In someaspects, the crystallization inhibitor or crystal growth inhibitor is apolymer. In some aspects, the polymer is polyvinylpyrrolidone. In someaspects, the polymer is polyvinylpyrrolidone K90. In some aspects, thepolymer is polyvinylpyrrolidone K30. In some aspects, the polymer ishydroxypropyl methylcellulose. In some aspects, the polymer is polyvinylacetate. In some aspects, the polymer is a cyclodextrin. In someaspects, the cyclodextrin is hydroxypropyl β-cyclodextrin.

In some aspects, the one or more excipients comprise a suspending agent.In some aspects, the suspending agent is selected from the groupconsisting of: hydroxyethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, microcrystallinecellulose, sodium carboxymethylcellulose, xanthan gum, acacia, analginate, and guar gum. In some aspects, the suspending agent comprisesa thickening agent.

In some aspects, the suspending agent is present in an amount of 0.1 to15 wt/wt %.

In some aspects, the one or more excipients comprise a pH modifyingagent. In some aspects, the pH modifying agent is selected from thegroup consisting of: citric acid, sodium citrate, acetic acid, sodiumacetate, sodium hydroxide, sodium dihydrogen phosphate, and disodiumhydrogen phosphate.

In some aspects, the one or more excipients comprise an emulsifyingagent selected from the group consisting of: a polysorbate, cetostearylalcohol, and cetyl alcohol.

In some aspects, the one or more excipients comprise an antioxidant. Insome aspects, the antioxidant is selected from the group consisting of:butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid,tocopherol, and vitamin E.

In some aspects, the pharmaceutical composition comprises an antioxidantin an amount of less than 10 wt/wt %.

In some aspects, the one or more excipients comprise a chelating agent.In some aspects, the chelating agent is ethylenediaminetetraacetic acid.In some aspects, the chelating agent is a disodium salt ofethylenediaminetetraacetic acid.

In some aspects, the one or more excipients comprise a preservative. Insome aspects, the preservative is selected from the group consisting of:methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzoicacid, sodium benzoate, and benzalkonium chloride.

In some aspects, the pharmaceutical composition comprises a preservativein an amount of less than 10 wt/wt %.

In some aspects, the one or more excipients comprise an antifoamingagent. In some aspects, the pharmaceutical composition comprises anantifoaming agent in an amount of less than 10 wt/wt %.

In some aspects, the one or more excipients comprise a solubilizer. Insome aspects, the solubilizer is cremophor. In some aspects, thesolubilizer is vitamin E. In some aspects, the solubilizer ispolyethylene glycol. In some aspects, the solubilizer is propyleneglycol. In some aspects, the solubilizer comprises a co-solvent.

In some aspects, the one or more excipients comprise a vehicle. In someaspects, the vehicle is selected from the group consisting of: water,ethanol, glycerol, propylene glycol, polyethylene glycol, and an oil.

In some aspects, the one or more excipients comprise a surfactant or awetting agent. In some aspects, the surfactant or wetting agent isselected from the group consisting of: a polysorbate, a polyoxamer, andsodium lauryl sulfate.

In some aspects, the one or more excipients comprise a sweetener. Insome aspects, the sweetener is selected from the list consisting of:sorbitol, mannitol, xylitol, aspartame, sucralose, saccharine, andacesulfame K.

In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 10 wt/wt %.

In some aspects, the one or more excipients comprise a stabilizer.

In some aspects, the one or more excipients comprise a flavoring agent.In some aspects, the flavoring agent is selected from the listconsisting of: an apple flavoring agent, an orange flavoring agent, amint flavoring agent, a cherry flavoring agent, and a strawberryflavoring agent.

In some aspects, the pharmaceutical composition comprises a flavoringagent in an amount of less than 10 wt/wt %.

In some aspects, the one or more excipients comprise a colorant.

Free from Impurities

In some aspects, the pharmaceutical composition comprises less than 5wt/wt % of all impurities relative to the mass of losartan.

In some aspects, the pharmaceutical composition comprises less than 5wt/wt % of an impurity relative to the mass of losartan.

In some aspects, the impurity is a product of losartan oxidation.

In some aspects, the impurity is a product of losartan degradation.

In some aspects, the impurity is a side product of a method of losartansynthesis.

In some aspects, the impurity is a byproduct of a method of losartansynthesis.

In some aspects, the impurity is losartan carboxylic acid.

In some aspects, the impurity is losartan impurity D. In some aspects,the pharmaceutical composition comprises less than 5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises about 0.01 to 5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises about 0.1 to 5 wt/wt % of losartanimpurity D relative to the mass of losartan.

In some aspects, the impurity is losartan impurity E. In some aspects,the pharmaceutical composition comprises less than 5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises about 0.01 to 5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises about 0.1 to 5 wt/wt % of losartanimpurity E relative to the mass of losartan.

In some aspects, the impurity is a biological contaminant. In someaspects, the impurity is a living biological contaminant. In someaspects, the impurity is a dead biological contaminant. In some aspects,the impurity is a viral contaminant. In some aspects, the impurity is afungal contaminant. In some aspects, the impurity is a bacterialcontaminant. In some aspects, the impurity is a bacterial endotoxin.

In some aspects, the biological contaminant is a replication-competent,metabolically inactive or minimally active biological product. In someaspects, the replication-competent, metabolically inactive or minimallyactive biological product is a spore.

In some aspects, the impurity is pyrogenic.

In some aspects, the impurity is detectable as visible particulatematter.

Sterility

In some aspects, the pharmaceutical composition has been subjected to asterilizing treatment. In some aspects, one or more components of thepharmaceutical composition have been subjected to a sterilizingtreatment.

In some aspects, the sterilizing treatment comprises filtration. In someaspects, the sterilizing treatment comprises exposure to a hightemperature. In some aspects, the sterilizing treatment comprisesexposure to a low temperature. In some aspects, the sterilizingtreatment comprises application of ultraviolet radiation. In someaspects, the sterilizing treatment is sufficient to kill a livingbiological contaminant.

Stability

In some aspects, the pharmaceutically acceptable composition is stableas measured by one or more substantially unchanged characteristics afterstorage, the one or more substantially unchanged characteristicsselected from the group consisting of: the concentration of losartan inthe pharmaceutical composition; the concentration of an impurity in thepharmaceutical composition; the visual appearance of the pharmaceuticalcomposition; the viscosity of the pharmaceutical composition; theuniformity of the pharmaceutical composition; and the sedimentation rateof the pharmaceutical composition.

In some aspects, the pharmaceutical composition is stable at 2° C.-8° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 3 months at 2° C.-8° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for4 months at 2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 6 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 8 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 10 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 12 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 16 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 18 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 24 months at 2° C.-8° C. and≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable at 15° C.-25°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 3 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for4 months at 15° C.-25° C. and ≤65% relative humidity. In some aspects,the pharmaceutical composition is stable for 6 months at 15° C.-25° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 8 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for10 months at 15° C.-25° C. and ≤65% relative humidity. In some aspects,the pharmaceutical composition is stable for 12 months at 15° C.-25° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 16 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for18 months at 15° C.-25° C. and ≤65% relative humidity. In some aspects,the pharmaceutical composition is stable for 24 months at 15° C.-25° C.and ≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable at 30° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 3 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 4 months at 30° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 6 months at 30° C. and ≤65% relative humidity.In some aspects, the pharmaceutical composition is stable for 8 monthsat 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 10 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 12 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 16 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 18 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for24 months at 30° C. and ≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable at 40° C. and75% relative humidity. In some aspects, the pharmaceutical compositionis stable for 3 months at 40° C. and 75% relative humidity. In someaspects, the pharmaceutical composition is stable for 4 months at 40° C.and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 6 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 8 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 10 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 12 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 16 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 18 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 24 months at 40° C. and 75% relative humidity.

Liquid and Powder Forms

In some aspects, the pharmaceutical composition of the presentdisclosure is a solution, an emulsion, or a suspension. In some aspects,the present disclosure provides for a concentrated form of losartan or apharmaceutically acceptable salt thereof, which can be combined with asuitable diluent to prepare a pharmaceutical composition describedherein. In some aspects, the concentrated form of losartan or apharmaceutically acceptable salt thereof is selected from the groupconsisting of: a powder, a plurality of granules, modified losartan, anda concentrated liquid form (e.g., a concentrated solution or alow-volume mixed solid and liquid phase). In some aspects, theconcentrated form of losartan or a pharmaceutically acceptable saltthereof can be combined with a suitable diluent to prepare one or moreof a solution, a suspension, and an emulsion.

In some aspects, the concentrated form of losartan or a pharmaceuticallyacceptable salt thereof is combined with the suitable diluent and heatedto form a pharmaceutically acceptable composition disclosed herein. Insome aspects, the concentrated form of losartan or a pharmaceuticallyacceptable salt thereof is combined with the suitable diluent and anadditional component to form a pharmaceutically acceptable compositiondisclosed herein. In some aspects, the additional component is a pHmodifying agent. In some aspects, the pH modifying agent is an acid. Insome aspects, the pH modifying agent is a base.

Solution

In some aspects, the pharmaceutical composition is a solution. In someaspects, the pharmaceutical composition is a solution and thepharmaceutical composition comprises losartan. In some aspects, thepharmaceutical composition is a solution and the pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of losartan. Insome aspects, the pharmaceutical composition is a solution and thepharmaceutical composition comprises losartan potassium.

In some aspects, the pharmaceutical composition is a solution comprisinglosartan substantially dissolved in a pharmaceutically acceptablevehicle. In some aspects, the solution comprises at least 75% oflosartan or pharmaceutically acceptable salt thereof in dissolved form.In some aspects, the solution comprises at least 90% of losartan orpharmaceutically acceptable salt thereof in dissolved form.

In some aspects, the solution further comprises one or more inactiveingredients selected from the group consisting of: co-solvents, pHmodifying agents, surfactants, antioxidants, preservatives, andflavoring agents.

Emulsion

In some aspects, the pharmaceutical composition is an emulsion. In someaspects, the pharmaceutical composition is an emulsion and thepharmaceutical composition comprises losartan. In some aspects, thepharmaceutical composition is an emulsion and the pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of losartan. Insome aspects, the pharmaceutical composition is an emulsion and thepharmaceutical composition comprises losartan potassium.

In some aspects, the emulsion is a multiple emulsion. In some aspect,the emulsion is a microemulsion.

In some aspects, the emulsion comprises at least two immiscible liquidphases wherein one liquid phase is in the form of globules. In someaspects, the pharmaceutical composition comprises an emulsifying agent.In some aspects, the pharmaceutical composition is an emulsion wherein ahydrophobic phase comprises at least 50% of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition is an emulsion wherein a hydrophobic phasecomprises at least 60% of losartan or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition is an emulsionwherein a hydrophobic phase comprises at least 70% of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition is an emulsion wherein a hydrophobic phasecomprises at least 80% of losartan or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition is an emulsionwherein a hydrophobic phase comprises at least 90% of losartan or apharmaceutically acceptable salt thereof.

Suspension

In some aspects, the pharmaceutical composition is a suspension. In someaspects, the pharmaceutical composition is a suspension and thepharmaceutical composition comprises losartan. In some aspects, thepharmaceutical composition is a suspension and the pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of losartan. Insome aspects, the pharmaceutical composition is a suspension and thepharmaceutical composition comprises losartan potassium.

In some aspects, the suspension is a cloudy biphasic liquid comprising aplurality of losartan particles uniformly dispersed in apharmaceutically acceptable vehicle. In some aspects, at least 50% oflosartan or pharmaceutically acceptable salt thereof is in suspendedform. In some aspects, at least 60% of losartan or pharmaceuticallyacceptable salt thereof is in suspended form. In some aspects, at least70% of losartan or pharmaceutically acceptable salt thereof is insuspended form. In some aspects, at least 80% of losartan orpharmaceutically acceptable salt thereof is in suspended form. In someaspects, at least 90% of losartan or pharmaceutically acceptable saltthereof is in suspended form.

In some aspects, the suspension comprises a flocculating agent.

Powder

In some aspects, the present disclosure provides a powder which iscombined with a liquid to produce the pharmaceutical compositiondescribed herein.

In some aspects, the powder comprises losartan or a pharmaceuticallyacceptable salt thereof. In some aspects, the powder comprises losartan.In some aspects, the powder comprises losartan potassium.

In some aspects, the powder comprises one or more pharmaceuticallyacceptable excipients.

In some aspects, the losartan powder is bioequivalent to COZAAR®.

In some aspects, the powder is sterile.

In some aspects, the powder is non-pyrogenic.

In some aspects, the powder is substantially free of impurities.

In some aspects, the liquid is a solvent. In some aspects, the solventis water.

In some aspects, the liquid is provided in a container. In some aspects,the container is a bottle. In some aspects, the bottle is an amberbottle.

In some aspects, the container contains a suspending agent. In someaspects, the container contains a preservative. In some aspects, thecontainer contains a sweetener. In some aspects, the container containsa flavoring agent.

In some aspects, the powder is packaged in a sachet.

Granules

In some aspects, the present disclosure provides a plurality of granuleswhich is combined with a liquid to produce the pharmaceuticalcomposition described herein.

In some aspects, the plurality of granules comprises losartan or apharmaceutically acceptable salt thereof. In some aspects, the pluralityof granules comprises losartan. In some aspects, the plurality ofgranules comprises losartan potassium.

In some aspects, the plurality of granules comprises one or morepharmaceutically acceptable excipients.

In some aspects, the plurality of granules is bioequivalent to COZAAR®.

In some aspects, the plurality of granules is sterile.

In some aspects, the plurality of granules is non-pyrogenic.

In some aspects, the plurality of granules is substantially free ofimpurities.

In some aspects, the liquid is a solvent. In some aspects, the solventis water.

In some aspects, the liquid is provided in a container. In some aspects,the container is a bottle. In some aspects, the bottle is an amberbottle.

In some aspects, the container contains a suspending agent. In someaspects, the container contains a preservative. In some aspects, thecontainer contains a sweetener. In some aspects, the container containsa flavoring agent.

In some aspects, the plurality of granules is packaged in a sachet.

Particle Characterization

In some aspects, the suspension or the powder exhibits a dissolutionprofile as measured using a paddle type apparatus. In some aspects, thedissolution profile is measured at 50 rpm. In some aspects, thedissolution profile of the suspension or powder is measured in a mixtureof water and 0.1N HCl. In some aspects, less than 35% of the pluralityof losartan particles are dissolved in 15 minutes. In some aspects, lessthan 70% of the plurality of losartan particles are dissolved in 30minutes. In some aspects, at least 80% of the plurality of losartanparticles are dissolved in 60 minutes. In some aspects, at least 80% ofthe plurality of losartan particles are dissolved in 15 minutes. In someaspects, at least 85% of the plurality of losartan particles aredissolved in 15 minutes. In some aspects, at least 90% of the pluralityof losartan particles are dissolved in 15 minutes. In some aspects, atleast 95% of the plurality of losartan particles are dissolved in 15minutes. In some aspects, about 100% of the plurality of losartanparticles are dissolved in 15 minutes. In some aspects, at least 80% ofthe plurality of losartan particles are dissolved in 5 minutes. In someaspects, at least 85% of the plurality of losartan particles aredissolved in 5 minutes. In some aspects, at least 90% of the pluralityof losartan particles are dissolved in 5 minutes. In some aspects, atleast 95% of the plurality of losartan particles are dissolved in 5minutes. In some aspects, about 100% of the plurality of losartanparticles are dissolved in 5 minutes.

In some aspects, the suspension or powder exhibits a particle sizedistribution as measured using a particle size analyzer. In someaspects, the particle size analyzer is a Malvern Mastersizer particlesize analyzer. In some aspects, the particle size analyzer is a MalvernMastersizer 3000 particle size analyzer. In some aspects, the particlesize analyzer is a Malvern Zetasizer particle size analyzer.

In some aspects, the particle size distribution comprises a D10 valueless than 100 μm. In some aspects, the particle size distributioncomprises a D50 value less than 500 μm. In some aspects, the particlesize distribution comprises a D90 value less than 1000 μm. In someaspects, the particle size distribution comprises a D10 value less than100 μm, a D50 value less than 500 μm, and a D90 value less than 1000 μm.

In some aspects, the particle size distribution comprises a D10 valueless than 20 μm. In some aspects, the particle size distributioncomprises a D50 value less than 100 μm. In some aspects, the particlesize distribution comprises a D90 value less than 300 μm. In someaspects, the particle size distribution comprises a D10 value less than20 μm, a D50 value less than 100 μm, and a D90 value less than 300 μm.

In some aspects, the particle size distribution comprises a D10 valueless than 2 μm. In some aspects, the particle size distributioncomprises a D50 value less than 10 μm. In some aspects, the particlesize distribution comprises a D90 value less than 30 μm. In someaspects, the particle size distribution comprises a D10 value less than2 μm, a D50 value less than 10 μm, and a D90 value less than 30 μm.

In some aspects, the particle size distribution comprises a D10 valueless than 100 nm. In some aspects, the particle size distributioncomprises a D50 value less than 500 nm. In some aspects, the particlesize distribution comprises a D90 value less than 1000 nm. In someaspects, the particle size distribution comprises a D10 value less than100 nm, a D50 value less than 500 nm, and a D90 value less than 1000 nm.

In some aspects, the particle size distribution comprises a D90 valueless than 2 μm. In some aspects, the particle size distributioncomprises a D90 value less than 1 μm. In some aspects, the particle sizedistribution comprises a D90 value less than 500 nm.

In some aspects, the particle size distribution comprises a D10 valueless than or equal to 1 μm. In some aspects, the particle sizedistribution comprises a D50 value less than or equal to 5 μm. In someaspects, the particle size distribution comprises a D90 value less thanor equal to 15 μm. In some aspects, the particle size distributioncomprises a D10 value less than or equal to 1 μm, a D50 value less thanor equal to 5 μm, and a D90 value less than or equal to 15 μm.

In some aspects, the suspension or the powder has a sedimentation rateof less than 10% over a period of 24 hours. In some aspects, thesuspension or the powder has a sedimentation rate of less than 5% over aperiod of 24 hours.

Modified Losartan

In some aspects, the pharmaceutical composition comprises a modifiedlosartan. In some aspects, the powder comprises a modified losartan. Insome aspects, the modified losartan comprises losartan or apharmaceutically acceptable salt thereof complexed or coated with a wax,one or more polymers, or one or more other inactive ingredients. In someaspects, the modified losartan comprises losartan or a pharmaceuticallyacceptable salt thereof complexed or coated with a wax. In some aspects,the modified losartan comprises losartan or a pharmaceuticallyacceptable salt thereof complexed or coated with one or more polymers.In some aspects, the modified losartan is losartan or a pharmaceuticallyacceptable salt thereof coated with one or more inactive ingredients.

Crystalline Form

In some aspects, the powder or suspension comprises losartan or apharmaceutically acceptable salt thereof in crystalline form. In someaspects, the crystalline form is thermodynamically stable. In someaspects, the crystalline form is thermodynamically stable, as measuredby a substantially unchanged X-ray powder diffraction (XRPD) profilefollowing storage. In some aspects, the crystalline form isthermodynamically stable, as measured by a substantially unchangeddifferential scanning calorimetry (DSC) profile following storage.

Concentration of Losartan

In some aspects, the pharmaceutical composition comprises about 1 mg/mLto about 50 mg/mL of losartan or pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprises about2 mg/mL to about 20 mg/mL of losartan or a pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprisesabout 5 mg/mL to about 20 mg/mL of losartan or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprises about 8 mg/mL to about 12 mg/mL of losartan or apharmaceutically acceptable salt thereof.

pH

In some aspects, the pharmaceutical composition has a pH between 2 and10. In some aspects, the pharmaceutical composition has a pH between 2and 7. In some aspects, the pharmaceutical composition has a pH of about6. In some aspects, the pharmaceutical composition has a pH of about 4.In some aspects, the pharmaceutical composition has a pH of 4.2. In someaspects, the pharmaceutical composition has a pH of about 5. In someaspects, the pharmaceutical composition has a pH less than 6. In someaspects, the pharmaceutical composition has a pH greater than 6. In someaspects, the pharmaceutical composition has a pH between 7 and 9. Insome aspects, the pharmaceutical composition has a pH between 3 and 5.In some aspects, the pharmaceutical composition has a pH between 5 and7.

Pharmacokinetic Parameters and Bioequivalence

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 98% to about 102% of the mean T_(max) ofCOZAAR®. In some aspects, the mean T_(max) of the pharmaceuticalcomposition described herein is about 95% to about 105% of the meanT_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 90% to about 110%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 80% to about 125%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 75% to about 130%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 70% to about 135%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 65% to about 140%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 60% to about 145%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about100%, about 105%, about 110%, about 115%, about 120% about 125%, about130%, about 135%, about 140%, or about 145% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 50% to about 150% of the mean T_(max) ofCOZAAR®. In some aspects, the mean T_(max) of the pharmaceuticalcomposition described herein is about 40% to about 160% of the meanT_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 30% to about 170%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 20% to about 200%of the mean T_(max) of COZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 98% to about 102% of the mean C_(max) ofCOZAAR®. In some aspects, the mean C_(max) of the pharmaceuticalcomposition described herein is about 95% to about 105% of the meanC_(max) of COZAAR®. In some aspects, the mean C_(max) of thepharmaceutical composition described herein is about 90% to about 110%of the mean C_(max) of COZAAR®. In some aspects, the mean C_(max) of thepharmaceutical composition described herein is about 80% to about 125%of the mean C_(max) of COZAAR®. In some aspects, the mean C_(max) of thepharmaceutical composition described herein is about 75% to about 130%of the mean C_(max) of COZAAR®. In some aspects, the mean C_(max) of thepharmaceutical composition described herein is about 70% to about 135%of the mean C_(max) of COZAAR®. In some aspects, the mean C_(max) of thepharmaceutical composition described herein is about 65% to about 140%of the mean C_(max) of COZAAR®. In some aspects, the mean C_(max) of thepharmaceutical composition described herein is about 60% to about 145%of the mean C_(max) of COZAAR®. In some aspects, the mean C_(max) of thepharmaceutical composition described herein is about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about100%, about 105%, about 110%, about 115%, about 120% about 125%, about130%, about 135%, about 140%, or about 145% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 98% to about 102% of the mean AUC_(0-∞) ofCOZAAR®. In some aspects, the mean AUC_(0-∞) of the pharmaceuticalcomposition described herein is about 95% to about 105% of the meanAUC_(0-∞) of COZAAR®. In some aspects, the mean AUC_(0-∞) of thepharmaceutical composition described herein is about 90% to about 110%of the mean AUC_(0-∞) of COZAAR®. In some aspects, the mean AUC_(0-∞) ofthe pharmaceutical composition described herein is about 80% to about125% of the mean AUC_(0-∞) of COZAAR®. In some aspects, the meanAUC_(0-∞) of the pharmaceutical composition described herein is about75% to about 130% of the mean AUC_(0-∞) of COZAAR®. In some aspects, themean AUC_(0-∞) of the pharmaceutical composition described herein isabout 70% to about 135% of the mean AUC_(0-∞) of COZAAR®. In someaspects, the mean AUC_(0-∞) of the pharmaceutical composition describedherein is about 65% to about 140% of the mean AUC_(0-∞) of COZAAR®. Insome aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 60% to about 145% of the mean AUC_(0-∞) ofCOZAAR®. In some aspects, the mean AUC_(0-∞) of the pharmaceuticalcomposition described herein is about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 105%,about 110%, about 115%, about 120% about 125%, about 130%, about 135%,about 140%, or about 145% of the mean AUC_(0-∞) of COZAAR®.

Additional Active Ingredients

In some aspects, the pharmaceutical composition comprises one or moreactive ingredients in addition to losartan or a pharmaceuticallyacceptable salt thereof. In some aspects, the one or more activeingredients are selected from the group consisting of: calcium channelblockers, diuretics, ACE inhibitors, and beta blockers. In some aspects,the one or more active ingredients are calcium channel blockers. In someaspects, the one or more active ingredients are diuretics. In someaspects, the one or more active ingredients are ACE inhibitors. In someaspects, the one or more active ingredients are beta blockers.

Viscosity

In some aspects, the pharmaceutical composition has a viscosity of lessthan 2000 centipoise, as measured using a Brookfield viscometer. In someaspects, the pharmaceutical composition has a viscosity of less than1000 centipoise, as measured using a Brookfield viscometer.

Volume

In some aspects, the pharmaceutical composition is administered in avolume of 0.5 mL to 50 mL. In some aspects, the pharmaceuticalcomposition is administered in a volume of less than 100 mL. In someaspects, the pharmaceutical composition is administered in a volume ofabout 2.5 mL, about 5 mL, or about 10 mL.

Container

In some aspects, a pharmaceutical composition is packaged in a glasscontainer. In some aspects, the powder is packaged in a glass container.In some aspects, the glass container is an amber glass container. Insome aspects, the amber glass container is child resistant. In someaspects, the amber glass container comprises a child resistant cap. Insome aspects, the pharmaceutical composition is packaged in a polymericcontainer. In some aspects, the polymeric container is child resistant.In some aspects, the polymeric container comprises a child resistantcap. In some aspects, the polymeric container comprises high densitypolyethylene (HDPE). In some aspects, the polymeric container compriseslow density polyethylene (LDPE).

Kit

In some aspects, the present disclosure provides for a kit comprising apharmaceutically acceptable composition described herein, and furthercomprising a set of instructions for administration of thepharmaceutically acceptable composition to a subject in need thereof. Insome aspects, the set of instructions comprises an instruction to add anamount of a diluent to a container comprising a concentrated form oflosartan or a pharmaceutically acceptable salt thereof, wherein the kitcomprises the container. In some aspects, the diluent is water.

In some aspects, the present disclosure provides for a kit comprising: aconcentrated form of losartan or a pharmaceutically acceptable saltthereof; a diluent; and a set of instructions, wherein the set ofinstructions comprises: instructions for combining the concentrated formof losartan or a pharmaceutically acceptable salt thereof and thediluent to form a pharmaceutically acceptable composition describedherein; and instructions for administration of the pharmaceuticallyacceptable composition to a subject in need thereof. In some aspects,the concentrated form of losartan or a pharmaceutically acceptable saltthereof is in the form of a powder or a plurality of granules.

In some aspects, the kit comprises a concentrated form of apharmaceutical composition disclosed herein. In some aspects, theconcentrated form is prepared by combining components of apharmaceutical composition disclosed herein without dilution to a finalconcentration suitable for administration to a subject. In some aspects,the concentrated form is a concentrated liquid form. In some aspects,the concentrated liquid form is a solution. In some aspects, theconcentrated liquid form is a suspension. In some aspects, theconcentrated form is a dry form. In some aspects, the dry form comprisesless than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% ofwater by weight of the dry form. In some aspects, the dry form is apowder or a plurality of granules.

Method of Preparing Suspension

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising combining a pluralityof losartan particles and a suspending agent. In some aspects, theplurality of losartan particles is combined with the suspending agent.

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising dissolving losartanor a pharmaceutically acceptable salt thereof in a suitable fluid (e.g.,water), adjusting the pH of the suitable liquid comprising losartan or apharmaceutically acceptable salt thereof, and combining the suitableliquid comprising losartan or a pharmaceutically acceptable salt thereofwith the remaining components of the suspension, thereby forming thesuspension.

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising combining losartan ora pharmaceutically acceptable salt thereof and one or more excipients,granulating the composition with a suitable fluid (e.g., water), dryingthe resulting composition to form a dry composition, and combining thedry composition with a suitable liquid, thereby forming the suspension.

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising a step of particlesize reduction. In some aspects, the step of particle size reductioncomprises wet milling. In some aspects, the step of particle sizereduction comprises microfluidization. In some aspects, the step ofparticle size reduction comprises homogenization. In some aspects, thestep of particle size reduction comprises nano-milling.

In some aspects, a pH modifying agent is added after the plurality oflosartan particles is combined with the suspending agent. In someaspects, the pH modifying agent is selected from the group consistingof: citric acid, sodium citrate, acetic acid, sodium acetate, sodiumhydroxide, dibasic calcium phosphate, sodium dihydrogen phosphate, anddisodium hydrogen phosphate. In some aspects, the pH modifying agent isa buffer.

In some aspects, the one or more polymers are sprayed by dissolving theone or more polymers in a volatile solvent. In some aspects, thevolatile solvent is selected from the group consisting of: ethanol,acetone, or isopropyl alcohol. In some aspects, the volatile solvent isethanol. In some aspects, the volatile solvent is acetone. In someaspects, the volatile solvent is isopropyl alcohol.

In some aspects, heated air is added to cause evaporation of thevolatile solvent. In some aspects, evaporation of the volatile solventcauses deposition of the one or more polymers onto the surface of aparticle comprising losartan or a pharmaceutically acceptable saltthereof. In some aspects, the particles comprising losartan or apharmaceutically acceptable salt thereof are dried to form a modifiedlosartan. In some aspects, the plurality of losartan particles isprovided as a modified losartan which is preformed. In some aspects, theplurality of losartan particles comprises losartan or a pharmaceuticallyacceptable salt thereof.

In some aspects, the plurality of losartan particles is fluidized in afluidized bed system, and are then coated with one or more polymers. Insome aspects, the plurality of losartan particles comprises losartan ora pharmaceutically acceptable salt thereof. In some aspects, theplurality of losartan particles has a particle size of less than 1000μm. In some aspects, the plurality of losartan particles has a particlesize of less than 750 μm. In some aspects, the plurality of losartanparticles has a particle size of less than 500 μm. In some aspects, theplurality of losartan particles has a particle size of less than 250 μm.

In some aspects, the one or more polymers comprise pH dependent polymers(e.g., Eudragit L, Eudragit S, or cellulose acetate phthalate) and/or pHindependent polymers (e.g., Eudragit RS, Eudragit RL, or celluloseacetate).

In some aspects, the modified losartan tastes less bitter than losartan.

In some aspects, the modified losartan is more stable than losartan.

Method of Preparing Solution or Emulsion

In some aspects, the present disclosure provides a method of preparing asolution or an emulsion described herein, comprising combining thecomponents of the solution or the emulsion.

In some aspects, losartan or a pharmaceutically acceptable salt thereofis dissolved in a hydrophobic phase (e.g., vegetable oil). In someaspects, an antioxidant is added to a hydrophobic phase. In someaspects, the hydrophobic phase comprising losartan or a pharmaceuticallyacceptable salt thereof is mixed with a hydrophilic phase. In someaspects, the hydrophilic phase comprises a sweetener. In some aspects,the hydrophilic phase comprises a flavoring agent. In some aspects, thehydrophilic phase comprises Polysorbate 80 and/or Tweens. In someaspects, the emulsion is prepared by combining and mixing thehydrophobic phase and the hydrophilic phase. In some aspects, thehydrophobic phase and hydrophilic phase are mixed at a high speed usinga homogenizer.

Method of Preparing Powder

In some aspects, the present disclosure provides a method of preparing apowder, the method comprising dry blending the components of apharmaceutical composition described herein. In some aspects, thepharmaceutical composition is a suspension described herein.

Method of Preparing Modified Losartan

In some aspects, the present disclosure provides a method of preparingmodified losartan, the method comprising complexing or coating losartanor a pharmaceutically acceptable salt thereof with a substance, whereinthe substance is a wax, a polymer, or one or more other inactiveingredients. In some aspects, the modified losartan is formed duringpreparation of the pharmaceutical composition. In some aspects, modifiedlosartan is formed by complexation with an ion exchange resin. In someaspects, modified losartan is formed by complexation with acyclodextrin. In some aspects, the modified losartan is prepared bymicroencapsulation of losartan or a pharmaceutically acceptable saltthereof in a coat of inactive ingredients.

Method of Treatment

In some aspects, the present disclosure provides a method of treating asubject in need thereof comprising administering to the subject atherapeutically effective amount of the pharmaceutical compositiondescribed herein.

In some aspects, the subject has been diagnosed with pre-hypertension orhypertension. In some aspects, the subject has been diagnosed withpre-hypertension. In some aspects, the subject has been diagnosed withhypertension. In some aspects, the subject has a history ofhypertension.

In some aspects, the subject has been diagnosed with left ventricularhypertrophy.

In some aspects, the subject has been diagnosed with both hypertensionand left ventricular hypertrophy.

In some aspects, the subject has been diagnosed with type 2 diabetes.

In some aspects, the subject has been diagnosed with nephropathy.

In some aspects, the subject has been diagnosed with diabeticnephropathy.

In some aspects, the subject has been diagnosed with proteinuria.

In some aspects, the subject exhibits a urinary albumin to creatinineratio of greater than or equal to 300 mg/g.

In some aspects, the subject has been diagnosed with an elevated serumcreatinine.

In some aspects, the pharmaceutical composition is co-administered withat least one other pharmaceutical agent. In some aspects, the at leastone pharmaceutical agent is an antihypertensive agent. In some aspects,the antihypertensive agent is selected from the group consisting of: anangiotensin II antagonist, an angiotensin converting enzyme inhibitor,or a neutral endopeptidase/angiotensin converting enzyme inhibitor. Insome aspects, the antihypertensive agent is an angiotensin IIantagonist. In some aspects, the antihypertensive agent is anangiotensin converting enzyme inhibitor. In some aspects, theantihypertensive agent is a neutral endopeptidase/angiotensin convertingenzyme inhibitor.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In case of conflict, thepresent application including the definitions will control. Unlessotherwise required by context, singular terms shall include pluralitiesand plural terms shall include the singular. All publications, patentsand other references mentioned herein are incorporated by reference intheir entireties for all purposes as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference.

Although methods and materials similar or equivalent to those describedherein can be used in practice or testing of the present disclosure,suitable methods and materials are described below. The materials,methods and examples are illustrative only and are not intended to belimiting. Other features and advantages of the disclosure will beapparent from the detailed description and from the claims.

In order to further define this disclosure, the following terms anddefinitions are provided.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. The terms “a” (or “an”), as wellas the terms “one or more,” and “at least one” can be usedinterchangeably herein. In certain aspects, the term “a” or “an” means“single.” In other aspects, the term “a” or “an” includes “two or more”or “multiple.”

The term “about” is used herein to mean approximately, roughly, around,or in the regions of. When the term “about” is used in conjunction witha numerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10 percent, up or down (higher or lower).

The term “and/or” where used herein is to be taken as specificdisclosure of each of the two specified features or components with orwithout the other. Thus, the term “and/or” as used in a phrase such as“A and/or B” herein is intended to include “A and B,” “A or B,” “A”(alone), and “B” (alone). Likewise, the term “and/or” as used in aphrase such as “A, B, and/or C” is intended to encompass each of thefollowing aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; Aand C; A and B; B and C; A (alone); B (alone); and C (alone).

The term “pharmaceutically acceptable” as used herein refers to thosecompounds, materials, compositions, formulations, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

The term “modified losartan” as used herein refers to losartan or apharmaceutically acceptable salt thereof, wherein losartan or apharmaceutically acceptable salt thereof is complexed or coated withinactive ingredients. In some aspects, a modified losartan is morestable than losartan or a pharmaceutically acceptable salt thereof notcomplexed or coated with inactive ingredients. In some aspects, asuspension comprising a modified losartan is more stable than asuspension comprising losartan or a pharmaceutically acceptable saltthereof not complexed or coated with inactive ingredients. In someaspects, a modified losartan is less soluble in water than losartan or apharmaceutically acceptable salt thereof not complexed or coated withinactive ingredients. In some aspects, a modified losartan is moreresistant to degradation or oxidation than losartan or apharmaceutically acceptable salt thereof not complexed or coated withinactive ingredients.

The term “excipient” refers to any substance, not itself a therapeuticagent, which may be used in a composition for delivery of an activetherapeutic agent to a subject or combined with an active therapeuticagent (e.g., to create a pharmaceutical composition) to improve itshandling or storage properties or to permit or facilitate formation of adose unit of the composition (e.g., formation of a hydrogel which maythen be optionally incorporated into a patch). Excipients include, butare not limited to, solvents, penetration enhancers, wetting agents,antioxidants, lubricants, emollients, substances added to improveappearance or texture of the composition and substances used to formhydrogels. Any such excipients can be used in any dosage forms accordingto the present disclosure. The foregoing classes of excipients are notmeant to be exhaustive but merely illustrative as a person of ordinaryskill in the art would recognize that additional types and combinationsof excipients could be used to achieve the desired goals for delivery ofa drug. The excipient can be an inert substance, an inactive substance,and/or a not medicinally active substance. The excipient can servevarious purposes. A person skilled in the art can select one or moreexcipients with respect to the particular desired properties by routineexperimentation and without any undue burden. The amount of eachexcipient used can vary within ranges conventional in the art.Techniques and excipients which can be used to formulate dosage formsare described in Handbook of Pharmaceutical Excipients, 6th edition,Rowe et al., Eds., American Pharmaceuticals Association and thePharmaceutical Press, publications department of the RoyalPharmaceutical Society of Great Britain (2009); and Remington: theScience and Practice of Pharmacy, 21th edition, Gennaro, Ed., LippincottWilliams & Wilkins (2005).

The term “effective amount” or “pharmaceutically effective amount” or“therapeutically effective amount” as used herein refers to the amountor quantity of a drug (e.g., losartan or a pharmaceutically acceptablesalt thereof) or pharmaceutically active substance which is sufficientto elicit the required or desired therapeutic response, or in otherwords, the amount which is sufficient to elicit an appreciablebiological response when administered to a patient.

The term “unit dosage form” or “unit dose composition” as used hereinrefers to a device containing a quantity of the therapeutic compound,said quantity being such that one or more predetermined units may beprovided as a single therapeutic administration.

The term “C_(max)” as used herein refers to the maximum plasmaconcentration of a drug after administration of the drug.

The term “T_(max)” as used herein refers to the time required to reachthe maximal plasma concentration C_(max) after administration of a drug.

The term “AUC” as used herein refers to the area under the curve of aplot of plasma concentration versus time following administration of adrug.

The term “AUC_(0-t)” as used herein refers to the area under the drugconcentration-time curve from time zero to the time of the lastmeasurable concentration (Ct).

The term “AUC_(0-∞)” as used herein refers to the area under the drugconcentration-time curve from time zero to infinity.

The term “steady state” as used herein means that the amount of the drugreaching the system is approximately the same as the amount of the drugleaving the system. Thus, at “steady-state,” the patient's bodyeliminates the drug at approximately the same rate that the drug becomesavailable to the patient's system through absorption into the bloodstream.

The term “mean” refers to an average value in a patient population. Forexample, a “mean C_(max)” refers to an average of the maximum plasmaconcentrations of a drug in a patient population.

The term “treating” or “treatment” as used herein refers to theadministration of a composition to a subject for therapeutic purposes.

The term “serum concentration” generally refers to the amount of a drugor other compound in the circulation, both bound to proteins andunbound, the latter of which generally corresponds to thetherapeutically active fraction.

The term “bioavailability” generally refers to the rate and extent towhich the active ingredient is absorbed from a drug product and becomesavailable at the site of action.

“Bioequivalence” is a term in pharmacokinetics generally used to assessthe expected in vivo biological equivalence of two proprietarypreparations of a drug. Two pharmaceutical products are bioequivalent ifthey are pharmaceutically equivalent and their bioavailabilities (rateand extent of availability) after administration in the same molar doseare similar to such a degree that their effects, with respect to bothefficacy and safety, can be expected to be essentially the same.Bioequivalence criteria include The United States Food and DrugAdministration (“FDA”) requirement for bioequivalence studies to havepercentage ratios of the test vs reference for C_(max) and AUC, at 90%confidence interval, between 80% and 125%.

The term “stable” as used herein means a composition is substantiallyunchanged after storage for a period of time under given storageconditions. In some aspects, a composition is “stable” if it meets theInternational Council for Harmonisation of Technical Requirements forPharmaceuticals for Human Use (ICH) requirements for stability. In someaspects, a composition is considered stable if after a period of atleast 12 months of storage at 15° C.-25° C. and ≤65% relative humidity,the concentration or integrity of carrier components or losartan or apharmaceutically acceptable salt thereof is substantially unchanged(e.g., a loss of no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%of losartan or a pharmaceutically acceptable salt thereof). Stabilitycan also be analyzed by subjecting composition to accelerated stabilityconditions for a shorter period of time (e.g., 6 months at 30° C. at 65%relative humidity, or 6 months at 40° C. and 75% relative humidity) andobserving no substantial change in the concentration of losartan or apharmaceutically acceptable salt thereof, or other components in thecomposition. In some aspects, a pharmaceutical composition is considered“stable” if it exhibits substantially the same characteristics beforeand after storage at a given temperature and relative humidity over agiven time, wherein the characteristics are one or more of: theconcentration of losartan or a pharmaceutically acceptable salt thereof,the concentration of an impurity, the appearance of the composition, theviscosity of the composition, the uniformity of the dosage form, or thesedimentation rate of the composition (for suspension products). In someaspects, the pharmaceutical composition is substantially free ofimpurities following storage.

As used herein, the terms “impurity” and “impurities” refer to anychemical entities (e.g., product of losartan oxidation or degradation)or microbial entities (e.g., a living or dead microbial species) presentin a pharmaceutical composition described herein, other than thedisclosed components of the pharmaceutical composition. In some aspects,an impurity is a change in the physical properties and/or chemicalstructure of losartan or a pharmaceutically acceptable salt thereof, dueto exposure to heat, oxidation, excipients, and/or time under storage.An impurity can alter the pharmacokinetic properties of thepharmaceutical composition (e.g., where the impurity is a chemicalderivative of losartan or a pharmaceutically acceptable salt thereof),the stability of the pharmaceutical composition, or the safety ofadministration of the pharmaceutical composition (e.g., where theimpurity is a pathogenic or pyrogenic microbial contaminant). In someaspects, the impurity is a side product or byproduct of a method oflosartan synthesis. In some aspects, an impurity is a product oflosartan oxidation or degradation, indicating a decrease in losartandosage, or formation of a chemical entity having a differentbioavailability than losartan. In some aspects, the impurity is apyrogenic microbial entity or product of a microbial entity.

As used herein, the term “wt/wt %” refers to the percentage, by mass, ofa component of a pharmaceutical composition described herein, relativeto the mass of the entire pharmaceutical composition, unless otherwisespecified (as in the case of “wt/wt % relative to the mass oflosartan”). For example, if a component is described as 10 wt/wt %, themass of the component is 10% of the mass of the entire compositionincluding the component.

As used herein, “wt/wt % relative to the mass of losartan” refers to thepercentage, by mass, of a component of a pharmaceutical compositiondescribed herein, relative to the mass of losartan present in thepharmaceutical composition. For example, if an impurity is described as“less than 2 wt/wt % relative to the mass of losartan”, the mass of theimpurity present in the pharmaceutical composition is less than 2% ofthe mass of losartan present in the pharmaceutical composition. It willbe understood by a person of ordinary skill in the art to which thisapplication pertains that “the mass of losartan” in this context refersto the mass of losartan, and does not include the counterions of a saltof losartan (e.g., if losartan in the form of losartan potassium isadded to form a composition).

As used herein, the term “wt/vol %” refers to the percentage, by mass,of a component of a liquid pharmaceutical composition described herein,relative to the volume of the entire liquid pharmaceutical composition,where the ratio corresponds to a number of grams of the component in a100 mL volume. For example, if a component is described as 10 wt/vol %,the ratio of the mass of the component relative to the volume of theliquid pharmaceutical composition is that of 100 mL of a liquidcomposition containing 10 grams of the component.

The term “losartan” refers to 2-butyl-4-chloro-1-((2′-(1H-tetrazol-5-yl)(1,1′-biphenyl)-4-yl) methyl)-1H-imidazole-5-methanol, having thefollowing chemical structure:

The term “losartan impurity D” refers to2-butyl-4-chloro-5-formylimidazole, also known as2-butyl-5-chloro-1H-imidazole-4-carboxaldehyde, having the followingchemical structure:

The term “losartan impurity E” refers to5-(4′-methylbiphenyl-2-yl)-1H-tetrazole, having the following chemicalstructure:

Losartan is marketed as a losartan potassium salt tablet formulationunder the trade name COZAAR®.

As used herein, the term “sedimentation rate” refers to the rate atwhich a suspended phase of a suspension settles to the surface of thecontainer.

As used herein, the term “liquid” when referring to a pharmaceuticalcomposition herein refers to a composition which is substantially aliquid. Liquid compositions of the present disclosure includesuspensions, which are substantially liquid, despite comprising solidparticles suspended in a liquid phase.

As used herein, the term “multiple emulsion” refers to a liquidcomposition comprising both oil-in-water and water-in-oil typeemulsions.

As used herein, the term “microemulsion” refers to a thermodynamicallystable emulsion. In some aspects, a microemulsion is transparent orslightly turbid. In some aspects, the dispersed phase of a microemulsionconsists of small droplets with a diameter of about 100 Å to about 1,000Å.

The terms “co-administration”, “co-administering”, or “co-administered”refer to administering a combination of therapeutic agents, such as, forexample, a combination of losartan and an anti-hypertensive drug. Thecombination can be administered as two separate entities, such as, forexample, in separate dosage forms, or as a single combination entity,such as, for example, in the same oral, liquid pharmaceuticalcomposition. One therapeutic agent (e.g., losartan or a pharmaceuticallyacceptable salt form thereof) can be administered before, concomitantly,or subsequently to the administering of the other therapeutic agent(e.g., an anti-hypertensive drug) to the subject.

DETAILED DESCRIPTION OF THE INVENTION Pharmaceutical Composition

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising losartan or a pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable excipients, whereinthe pharmaceutical composition is suitable for oral administration,liquid, substantially free of impurities, and stable for at least 12months. In some aspects, the pharmaceutical composition is bioequivalentto COZAAR®. In some aspects, the pharmaceutical composition is notbioequivalent to COZAAR®.

In some aspects, the present disclosure provides a pharmaceuticalcomposition comprising losartan or pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable excipients, whereinthe pharmaceutical composition is suitable for oral administration,liquid, bioequivalent to COZAAR®, substantially free of impurities, andstable for at least 12 months.

Forms of Losartan

In some aspects, the pharmaceutical composition comprises losartan.

In some aspects, the pharmaceutical composition comprises apharmaceutically acceptable salt of losartan. In some aspects, thepharmaceutical composition comprises losartan potassium. In someaspects, the pharmaceutical composition comprises a sodium salt oflosartan. In some aspects, the pharmaceutical composition comprises alithium salt of losartan.

Excipients

In some aspects, the pharmaceutical composition comprises one or morepharmaceutically acceptable excipients selected from the groupconsisting of: a suspending agent, a pH modifying agent, an emulsifyingagent, an antioxidant, a chelating agent, a preservative, an antifoamingagent, a solubilizer, a vehicle, a surfactant or wetting agent, asweetener, a stabilizer, a flavoring agent, and a colorant. In someaspects, the pharmaceutical composition comprises two or morepharmaceutically acceptable excipients selected from the groupconsisting of: a suspending agent, a pH modifying agent, an emulsifyingagent, an antioxidant, a chelating agent, a preservative, an antifoamingagent, a solubilizer, a vehicle, a surfactant or wetting agent, asweetener, a stabilizer, a flavoring agent, and a colorant.

In some aspects, the pharmaceutical composition comprises acrystallization inhibitor or a crystal growth inhibitor. In someaspects, the crystallization inhibitor or crystal growth inhibitor is apolymer. In some aspects, the polymer is polyvinylpyrrolidone. In someaspects, the polymer is polyvinylpyrrolidone K90. In some aspects, thepolymer is polyvinylpyrrolidone K30. In some aspects, the polymer ishydroxypropyl methylcellulose. In some aspects, the polymer is polyvinylacetate. In some aspects, the polymer is a cyclodextrin. In someaspects, the cyclodextrin is hydroxypropyl β-cyclodextrin.

In some aspects, the one or more excipients comprise a suspending agent.In some aspects, the suspending agent is selected from the groupconsisting of: hydroxyethylcellulose, methylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, microcrystallinecellulose, sodium carboxymethylcellulose, xanthan gum, acacia, analginate, and guar gum. In some aspects, the suspending agent ishydroxyethylcellulose.

In some aspects, the suspending agent is methylcellulose. In someaspects, the suspending agent is hydroxymethylcellulose. In someaspects, the suspending agent is hydroxypropylmethylcellulose. In someaspects, the suspending agent is microcrystalline cellulose. In someaspects, the suspending agent is sodium carboxymethylcellulose. In someaspects, the suspending agent is xanthan gum. In some aspects, thesuspending agent is acacia. In some aspects, the suspending agent is analginate. In some aspects, the suspending agent is guar gum. In someaspects, the suspending agent comprises a thickening agent.

In some aspects, the suspending agent is present in an amount of 0.1 to15 wt/wt %. In some aspects, the suspending agent is present in anamount of 0.5 to 10 wt/wt %. In some aspects, the suspending agent ispresent in an amount of 1 to 8 wt/wt %. In some aspects, the suspendingagent is present in an amount of 2 to 7 wt/wt %. In some aspects, thesuspending agent is present in an amount of 3 to 6 wt/wt %. In someaspects, the suspending agent is present in an amount of about 0.1,about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6,about 7, about 8, about 9, about 10, about 11, about 12, about 13, about14, or about 15 wt/wt %.

In some aspects, the suspending agent is present in an amount of 0.1 to15 wt/vol %. In some aspects, the suspending agent is present in anamount of 0.5 to 10 wt/vol %. In some aspects, the suspending agent ispresent in an amount of 1 to 8 wt/vol %. In some aspects, the suspendingagent is present in an amount of 2 to 7 wt/vol %. In some aspects, thesuspending agent is present in an amount of 3 to 6 wt/vol %. In someaspects, the suspending agent is present in an amount of about 0.1,about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6,about 7, about 8, about 9, about 10, about 11, about 12, about 13, about14, or about 15 wt/vol %.

In some aspects, the one or more excipients comprise a pH modifyingagent. In some aspects, the pH modifying agent is selected from thegroup consisting of: citric acid, sodium citrate, sodium hydroxide,sodium dihydrogen phosphate, and disodium hydrogen phosphate. In someaspects, the pH modifying agent is citric acid. In some aspects, the pHmodifying agent is sodium citrate. In some aspects, the pH modifyingagent is sodium hydroxide. In some aspects, the pH modifying agent issodium dihydrogen phosphate. In some aspects, the pH modifying agent isdisodium hydrogen phosphate.

In some aspects, the one or more excipients comprise an emulsifyingagent selected from the group consisting of: a polysorbate, cetostearylalcohol, and cetyl alcohol. In some aspects, the emulsifying agent is apolysorbate. In some aspects, the emulsifying agent is cetostearylalcohol. In some aspects, the emulsifying agent is cetyl alcohol.

In some aspects, the one or more excipients comprise an antioxidant. Insome aspects, the antioxidant is selected from the group consisting of:butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid,tocopherol, and vitamin E. In some aspects, the antioxidant is butylatedhydroxyanisole. In some aspects, the antioxidant is butylatedhydroxytoluene. In some aspects, the antioxidant is ascorbic acid. Insome aspects, the antioxidant is tocopherol. In some aspects, theantioxidant is vitamin E.

In some aspects, the pharmaceutical composition comprises an antioxidantin an amount of less than 10 wt/wt %. In some aspects, thepharmaceutical composition comprises an antioxidant in an amount of lessthan 9 wt/wt %. In some aspects, the pharmaceutical compositioncomprises an antioxidant in an amount of less than 8 wt/wt %. In someaspects, the pharmaceutical composition comprises an antioxidant in anamount of less than 7 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises an antioxidant in an amount of less than 6 wt/wt%. In some aspects, the pharmaceutical composition comprises anantioxidant in an amount of less than 5 wt/wt %. In some aspects, thepharmaceutical composition comprises an antioxidant in an amount of lessthan 4 wt/wt %. In some aspects, the pharmaceutical compositioncomprises an antioxidant in an amount of less than 3 wt/wt %. In someaspects, the pharmaceutical composition comprises an antioxidant in anamount of less than 2 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises an antioxidant in an amount of less than 1 wt/wt%.

In some aspects, the pharmaceutical composition comprises an antioxidantin an amount of less than 10 wt/vol %. In some aspects, thepharmaceutical composition comprises an antioxidant in an amount of lessthan 9 wt/vol %. In some aspects, the pharmaceutical compositioncomprises an antioxidant in an amount of less than 8 wt/vol %. In someaspects, the pharmaceutical composition comprises an antioxidant in anamount of less than 7 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises an antioxidant in an amount of less than 6 wt/vol%. In some aspects, the pharmaceutical composition comprises anantioxidant in an amount of less than 5 wt/vol %. In some aspects, thepharmaceutical composition comprises an antioxidant in an amount of lessthan 4 wt/vol %. In some aspects, the pharmaceutical compositioncomprises an antioxidant in an amount of less than 3 wt/vol %. In someaspects, the pharmaceutical composition comprises an antioxidant in anamount of less than 2 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises an antioxidant in an amount of less than 1 wt/vol%.

In some aspects, the one or more excipients comprise a chelating agent.In some aspects, the chelating agent is ethylenediaminetetraacetic acid.In some aspects, the chelating agent is a disodium salt ofethylenediaminetetraacetic acid.

In some aspects, the one or more excipients comprise a preservative. Insome aspects, the preservative is selected from the group consisting of:methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzoicacid, sodium benzoate, and benzalkonium chloride. In some aspects, thepreservative is methyl paraben. In some aspects, the preservative isethyl paraben. In some aspects, the preservative is propyl paraben. Insome aspects, the preservative is butyl paraben. In some aspects, thepreservative is benzoic acid. In some aspects, the preservative issodium benzoate. In some aspects, the preservative is benzalkoniumchloride.

In some aspects, the pharmaceutical composition comprises a preservativein an amount of less than 10 wt/wt %. In some aspects, thepharmaceutical composition comprises a preservative in an amount of lessthan 9 wt/wt %. In some aspects, the pharmaceutical compositioncomprises a preservative in an amount of less than 8 wt/wt %. In someaspects, the pharmaceutical composition comprises a preservative in anamount of less than 7 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a preservative in an amount of less than 6 wt/wt%. In some aspects, the pharmaceutical composition comprises apreservative in an amount of less than 5 wt/wt %. In some aspects, thepharmaceutical composition comprises a preservative in an amount of lessthan 4 wt/wt %. In some aspects, the pharmaceutical compositioncomprises a preservative in an amount of less than 3 wt/wt %. In someaspects, the pharmaceutical composition comprises a preservative in anamount of less than 2 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a preservative in an amount of less than 1 wt/wt%.

In some aspects, the pharmaceutical composition comprises a preservativein an amount of less than 10 wt/vol %. In some aspects, thepharmaceutical composition comprises a preservative in an amount of lessthan 9 wt/vol %. In some aspects, the pharmaceutical compositioncomprises a preservative in an amount of less than 8 wt/vol %. In someaspects, the pharmaceutical composition comprises a preservative in anamount of less than 7 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises a preservative in an amount of less than 6 wt/vol%. In some aspects, the pharmaceutical composition comprises apreservative in an amount of less than 5 wt/vol %. In some aspects, thepharmaceutical composition comprises a preservative in an amount of lessthan 4 wt/vol %. In some aspects, the pharmaceutical compositioncomprises a preservative in an amount of less than 3 wt/vol %. In someaspects, the pharmaceutical composition comprises a preservative in anamount of less than 2 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises a preservative in an amount of less than 1 wt/vol%.

In some aspects, the one or more excipients comprise an antifoamingagent. In some aspects, the pharmaceutical composition comprises anantifoaming agent in an amount of less than 10 wt/wt %. In some aspects,the pharmaceutical composition comprises an antifoaming agent in anamount of less than 9 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises an antifoaming agent in an amount of less than 8wt/wt %. In some aspects, the pharmaceutical composition comprises anantifoaming agent in an amount of less than 7 wt/wt %. In some aspects,the pharmaceutical composition comprises an antifoaming agent in anamount of less than 6 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises an antifoaming agent in an amount of less than 5wt/wt %. In some aspects, the pharmaceutical composition comprises anantifoaming agent in an amount of less than 4 wt/wt %. In some aspects,the pharmaceutical composition comprises an antifoaming agent in anamount of less than 3 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises an antifoaming agent in an amount of less than 2wt/wt %. In some aspects, the pharmaceutical composition comprises anantifoaming agent in an amount of less than 1 wt/wt %.

In some aspects, the one or more excipients comprise an antifoamingagent. In some aspects, the pharmaceutical composition comprises anantifoaming agent in an amount of less than 10 wt/vol %. In someaspects, the pharmaceutical composition comprises an antifoaming agentin an amount of less than 9 wt/vol %. In some aspects, thepharmaceutical composition comprises an antifoaming agent in an amountof less than 8 wt/vol %. In some aspects, the pharmaceutical compositioncomprises an antifoaming agent in an amount of less than 7 wt/vol %. Insome aspects, the pharmaceutical composition comprises an antifoamingagent in an amount of less than 6 wt/vol %. In some aspects, thepharmaceutical composition comprises an antifoaming agent in an amountof less than 5 wt/vol %. In some aspects, the pharmaceutical compositioncomprises an antifoaming agent in an amount of less than 4 wt/vol %. Insome aspects, the pharmaceutical composition comprises an antifoamingagent in an amount of less than 3 wt/vol %. In some aspects, thepharmaceutical composition comprises an antifoaming agent in an amountof less than 2 wt/vol %. In some aspects, the pharmaceutical compositioncomprises an antifoaming agent in an amount of less than 1 wt/vol %.

In some aspects, the one or more excipients comprise a solubilizer. Insome aspects, the solubilizer is cremophor. In some aspects, thesolubilizer is vitamin E. In some aspects, the solubilizer ispolyethylene glycol. In some aspects, the solubilizer is propyleneglycol. In some aspects, the solubilizer comprises a co-solvent.

In some aspects, the one or more excipients comprise a vehicle. In someaspects, the vehicle is selected from the group consisting of: water,ethanol, glycerol, propylene glycol, polyethylene glycol, and an oil. Insome aspects, the vehicle is water. In some aspects, the vehicle isethanol. In some aspects, the vehicle is glycerol. In some aspects, thevehicle is propylene glycol. In some aspects, the vehicle is an oil.

In some aspects, the one or more excipients comprise a surfactant or awetting agent. In some aspects, the surfactant or wetting agent isselected from the group consisting of: a polysorbate, a polyoxamer, andsodium lauryl sulfate. In some aspects, the surfactant or wetting agentis polysorbate. In some aspects, the surfactant or wetting agent is apolyoxamer. In some aspects, the surfactant or wetting agent is sodiumlauryl sulfate.

In some aspects, the one or more excipients comprise a sweetener. Insome aspects, the sweetener is selected from the list consisting of:sorbitol, mannitol, xylitol, aspartame, sucralose, saccharine, andacesulfame K. In some aspects, the sweetener is sorbitol. In someaspects, the sweetener is mannitol. In some aspects, the sweetener isxylitol. In some aspects, the sweetener is aspartame. In some aspects,the sweetener is sucralose. In some aspects, the sweetener issaccharine. In some aspects, the sweetener is acesulfame K.

In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 10 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 9 wt/wt %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 8 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 7 wt/wt %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 6 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 5 wt/wt %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 4 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 3 wt/wt %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 2 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 1 wt/wt %.

In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 10 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 9 wt/vol %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 8 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 7 wt/vol %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 6 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 5 wt/vol %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 4 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 3 wt/vol %.In some aspects, the pharmaceutical composition comprises a sweetener inan amount of less than 2 wt/vol %. In some aspects, the pharmaceuticalcomposition comprises a sweetener in an amount of less than 1 wt/vol %.

In some aspects, the one or more excipients comprise a stabilizer.

In some aspects, the one or more excipients comprise a flavoring agent.In some aspects, the flavoring agent is selected from the listconsisting of: an apple flavoring agent, an orange flavoring agent, amint flavoring agent, a cherry flavoring agent, and a strawberryflavoring agent. In some aspects, the flavoring agent is an appleflavoring agent. In some aspects, the flavoring agent is an orangeflavoring agent. In some aspects, the flavoring agent is a strawberryflavoring agent.

In some aspects, the pharmaceutical composition comprises a flavoringagent in an amount of less than 10 wt/wt %. In some aspects, thepharmaceutical composition comprises a flavoring agent in an amount ofless than 9 wt/wt %. In some aspects, the pharmaceutical compositioncomprises a flavoring agent in an amount of less than 8 wt/wt %. In someaspects, the pharmaceutical composition comprises a flavoring agent inan amount of less than 7 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a flavoring agent in an amount of less than 6wt/wt %. In some aspects, the pharmaceutical composition comprises aflavoring agent in an amount of less than 5 wt/wt %. In some aspects,the pharmaceutical composition comprises a flavoring agent in an amountof less than 4 wt/wt %. In some aspects, the pharmaceutical compositioncomprises a flavoring agent in an amount of less than 3 wt/wt %. In someaspects, the pharmaceutical composition comprises a flavoring agent inan amount of less than 2 wt/wt %. In some aspects, the pharmaceuticalcomposition comprises a flavoring agent in an amount of less than 1wt/wt %.

In some aspects, the pharmaceutical composition comprises a flavoringagent in an amount of less than 10 wt/vol %. In some aspects, thepharmaceutical composition comprises a flavoring agent in an amount ofless than 9 wt/vol %. In some aspects, the pharmaceutical compositioncomprises a flavoring agent in an amount of less than 8 wt/vol %. Insome aspects, the pharmaceutical composition comprises a flavoring agentin an amount of less than 7 wt/vol %. In some aspects, thepharmaceutical composition comprises a flavoring agent in an amount ofless than 6 wt/vol %. In some aspects, the pharmaceutical compositioncomprises a flavoring agent in an amount of less than 5 wt/vol %. Insome aspects, the pharmaceutical composition comprises a flavoring agentin an amount of less than 4 wt/vol %. In some aspects, thepharmaceutical composition comprises a flavoring agent in an amount ofless than 3 wt/vol %. In some aspects, the pharmaceutical compositioncomprises a flavoring agent in an amount of less than 2 wt/vol %. Insome aspects, the pharmaceutical composition comprises a flavoring agentin an amount of less than 1 wt/vol %.

In some aspects, the one or more excipients comprise a colorant.

Free from Impurities

In some aspects, the pharmaceutical composition is substantially free ofimpurities.

In some aspects, the pharmaceutical composition comprises less than 5wt/wt % of all impurities relative to the mass of losartan. In someaspects, the pharmaceutical composition comprises less than 4.5 wt/wt %of all impurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 4 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 3.5 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 3 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 2.5 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 2 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.5 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.9 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.8 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.7 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.6 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.5 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.4 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.3 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.2 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.1 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.08 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.05 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.03 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.02 wt/wt % of allimpurities relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.01 wt/wt % of allimpurities relative to the mass of losartan.

In some aspects, the pharmaceutical composition comprises less than 5wt/wt % of an impurity relative to the mass of losartan. In someaspects, the pharmaceutical composition comprises less than 4.5 wt/wt %of an impurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 4 wt/wt % of an impurityrelative to the mass of losartan. In some aspects, the pharmaceuticalcomposition comprises less than 3.5 wt/wt % of an impurity relative tothe mass of losartan. In some aspects, the pharmaceutical compositioncomprises less than 3 wt/wt % of an impurity relative to the mass oflosartan. In some aspects, the pharmaceutical composition comprises lessthan 2.5 wt/wt % of an impurity relative to the mass of losartan. Insome aspects, the pharmaceutical composition comprises less than 2 wt/wt% of an impurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.5 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1 wt/wt % of an impurityrelative to the mass of losartan. In some aspects, the pharmaceuticalcomposition comprises less than 0.9 wt/wt % of an impurity relative tothe mass of losartan. In some aspects, the pharmaceutical compositioncomprises less than 0.8 wt/wt % of an impurity relative to the mass oflosartan. In some aspects, the pharmaceutical composition comprises lessthan 0.7 wt/wt % of an impurity relative to the mass of losartan. Insome aspects, the pharmaceutical composition comprises less than 0.6wt/wt % of an impurity relative to the mass of losartan. In someaspects, the pharmaceutical composition comprises less than 0.5 wt/wt %of an impurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.4 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.3 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.2 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.1 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.08 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.05 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.03 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.02 wt/wt % of animpurity relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.01 wt/wt % of animpurity relative to the mass of losartan.

In some aspect the impurity is a product of losartan oxidation.

In some aspects, the impurity is a product of losartan degradation.

In some aspects, the impurity is a side product of a method of losartansynthesis.

In some aspects, the impurity is a byproduct of a method of losartansynthesis.

In some aspects, the impurity is losartan carboxylic acid.

In some aspects, the impurity is losartan impurity D. In some aspects,the pharmaceutical composition comprises less than 5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 4.5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 4 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 3.5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 3 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 2.5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 2 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.9 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.8 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.7 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.6 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.4 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.3 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.2 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.1 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.9 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.8 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.7 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.6 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.5 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.4 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.3 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.2 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.1 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.05 wt/wt % of losartanimpurity D relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.01 wt/wt % of losartanimpurity D relative to the mass of losartan.

In some aspects, the impurity is losartan impurity E. In some aspects,the pharmaceutical composition comprises less than 5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 4.5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 4 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 3.5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 3 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 2.5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 2 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.9 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.8 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.7 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.6 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.4 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.3 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.2 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1.1 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 1 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.9 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.8 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.7 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.6 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.5 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.4 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.3 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.2 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.1 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.05 wt/wt % of losartanimpurity E relative to the mass of losartan. In some aspects, thepharmaceutical composition comprises less than 0.01 wt/wt % of losartanimpurity E relative to the mass of losartan.

In some aspects, the impurity is a biological contaminant. In someaspects, the impurity is a living biological contaminant. In someaspects, the impurity is a dead biological contaminant. In some aspects,the impurity is a viral contaminant. In some aspects, the impurity is afungal contaminant. In some aspects, the impurity is a bacterialcontaminant. In some aspects, the impurity is a bacterial endotoxin.

In some aspects, the biological contaminant is a replication-competent,metabolically inactive or minimally active biological product. In someaspects, the replication-competent, metabolically inactive or minimallyactive biological product is a spore.

In some aspects, the impurity is pyrogenic.

In some aspects, the impurity is detectable as visible particulatematter.

Sterility

In some aspects, the pharmaceutical composition has been subjected to asterilizing treatment. In some aspects, one or more components of thepharmaceutical composition have been subjected to a sterilizingtreatment.

In some aspects, the sterilizing treatment comprises filtration. In someaspects, the sterilizing treatment comprises exposure to a hightemperature. In some aspects, the sterilizing treatment comprisesexposure to a low temperature. In some aspects, the sterilizingtreatment comprises application of ultraviolet radiation. In someaspects, the sterilizing treatment is sufficient to kill a livingbiological contaminant.

Stability

In some aspects, the pharmaceutically acceptable composition is stableas measured by one or more substantially unchanged characteristics afterstorage, the one or more substantially unchanged characteristicsselected from the group consisting of: the concentration of losartan inthe pharmaceutical composition; the concentration of an impurity in thepharmaceutical composition; the visual appearance of the pharmaceuticalcomposition; the viscosity of the pharmaceutical composition; theuniformity of the pharmaceutical composition; and the sedimentation rateof the pharmaceutical composition. In some aspects, the one or moresubstantially unchanged characteristics comprise the concentration oflosartan in the pharmaceutical composition. In some aspects, the one ormore substantially unchanged characteristics comprise the concentrationof an impurity in the pharmaceutical composition. In some aspects, theone or more substantially unchanged characteristics comprise the visualappearance of the pharmaceutical composition. In some aspects, the oneor more substantially unchanged characteristics comprise the viscosityof the pharmaceutical composition. In some aspects, the one or moresubstantially unchanged characteristics comprise the uniformity of thepharmaceutical composition. In some aspects, the one or moresubstantially unchanged characteristics comprise the sedimentation rateof the pharmaceutical composition.

In some aspects, the pharmaceutical composition is stable at 2° C.-8° C.and ≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable for 1-24months at 2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 1-18 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 1-12 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 1-6 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 2-6 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 3-6 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 4-6 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 4-7 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 4-8 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 4-10 monthsat 2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 4-12 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 4-18 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 4-24 monthsat 2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 6-8 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 6-10 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 6-12 monthsat 2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 6-18 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 6-24 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 18-24 monthsat 2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 16-26 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 18-36 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 18-30 monthsat 2° C.-8° C. and ≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable for 2 monthsat 2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 3 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 4 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 5 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 6 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 7 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 8 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 9 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 10 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 11 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 12 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 16 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 18 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 19 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 20 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 21 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 22 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 23 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 24 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 25 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 26 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 27 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 28 months at 2° C.-8° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 29 months at 2° C.-8° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 30 months at2° C.-8° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 36 months at 2° C.-8° C. and≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable at 15° C.-25°C. and ≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable for 1-24months at 15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 1-18 months at 15° C.-25° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 1-12 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for1-6 months at 15° C.-25° C. and ≤65% relative humidity. In some aspects,the pharmaceutical composition is stable for 2-6 months at 15° C.-25° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 3-6 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for4-6 months at 15° C.-25° C. and ≤65% relative humidity. In some aspects,the pharmaceutical composition is stable for 4-7 months at 15° C.-25° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 4-8 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for4-10 months at 15° C.-25° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 4-12 months at 15°C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 4-18 months at 15° C.-25° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 4-24 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for6-8 months at 15° C.-25° C. and ≤65% relative humidity. In some aspects,the pharmaceutical composition is stable for 6-10 months at 15° C.-25°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 6-12 months at 15° C.-25° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for6-18 months at 15° C.-25° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 6-24 months at 15°C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 18-24 months at 15° C.-25° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 16-26 months at 15° C.-25° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 18-36 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 18-30 monthsat 15° C.-25° C. and ≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable for 2 monthsat 15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 3 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 4 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 5 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 6 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 7 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 8 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 9 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 10 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 11 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 12 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 16 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 18 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 19 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 20 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 21 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 22 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 23 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 24 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 25 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 26 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 27 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 28 months at 15° C.-25° C. and≤65% relative humidity. In some aspects, the pharmaceutical compositionis stable for 29 months at 15° C.-25° C. and ≤65% relative humidity. Insome aspects, the pharmaceutical composition is stable for 30 months at15° C.-25° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 36 months at 15° C.-25° C. and≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable at 30° C. and≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable for 1-24months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 1-18 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 1-12 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 1-6 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 2-6 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for3-6 months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 4-6 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 4-7 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 4-8 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 4-10 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for4-12 months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 4-18 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 4-24 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 6-8 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 6-10 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for6-12 months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 6-18 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 6-24 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 18-24 months at30° C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 16-26 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for18-36 months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 18-30 months at 30° C. and ≤65%relative humidity.

In some aspects, the pharmaceutical composition is stable for 2 monthsat 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 3 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 4 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 5 months at 30° C.and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 6 months at 30° C. and ≤65% relative humidity.In some aspects, the pharmaceutical composition is stable for 7 monthsat 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 8 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 9 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 10 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 11 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for12 months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 16 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 18 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 19 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 20 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for21 months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 22 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 23 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 24 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 25 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for26 months at 30° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 27 months at 30° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 28 months at 30° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 29 months at 30°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 30 months at 30° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for36 months at 30° C. and ≤65% relative humidity.

In some aspects, the pharmaceutical composition is stable at 40° C. and75% relative humidity.

In some aspects, the pharmaceutical composition is stable for 1-24months at 40° C. and 75% relative humidity. In some aspects, thepharmaceutical composition is stable for 1-18 months at 40° C. and 75%relative humidity. In some aspects, the pharmaceutical composition isstable for 1-12 months at 40° C. and 75% relative humidity. In someaspects, the pharmaceutical composition is stable for 1-6 months at 40°C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 2-6 months at 40° C. and 75% relativehumidity. In some aspects, the pharmaceutical composition is stable for3-6 months at 40° C. and 75% relative humidity. In some aspects, thepharmaceutical composition is stable for 4-6 months at 40° C. and 75%relative humidity. In some aspects, the pharmaceutical composition isstable for 4-7 months at 40° C. and 75% relative humidity. In someaspects, the pharmaceutical composition is stable for 4-8 months at 40°C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 4-10 months at 40° C. and 75% relativehumidity. In some aspects, the pharmaceutical composition is stable for4-12 months at 40° C. and 75% relative humidity. In some aspects, thepharmaceutical composition is stable for 4-18 months at 40° C. and 75%relative humidity. In some aspects, the pharmaceutical composition isstable for 4-24 months at 40° C. and 75% relative humidity. In someaspects, the pharmaceutical composition is stable for 6-8 months at 40°C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 6-10 months at 40° C. and 75% relativehumidity. In some aspects, the pharmaceutical composition is stable for6-12 months at 40° C. and 75% relative humidity. In some aspects, thepharmaceutical composition is stable for 6-18 months at 40° C. and 75%relative humidity. In some aspects, the pharmaceutical composition isstable for 6-24 months at 40° C. and 75% relative humidity. In someaspects, the pharmaceutical composition is stable for 18-24 months at40° C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 16-26 months at 40° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for18-36 months at 40° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 18-30 months at 40° C. and ≤65%relative humidity.

In some aspects, the pharmaceutical composition is stable at 40° C. and75% relative humidity. In some aspects, the pharmaceutical compositionis stable for 2 months at 40° C. and 75% relative humidity. In someaspects, the pharmaceutical composition is stable for 3 months at 40° C.and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 4 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 5 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 6 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 7 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 8 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 9 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 10 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 11 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 12 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 16 monthsat 40° C. and 75% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 18 months at 40° C. and 75% relative humidity.In some aspects, the pharmaceutical composition is stable for 19 monthsat 40° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 20 months at 40° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 21 months at 40° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 22 months at 40°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 23 months at 40° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for24 months at 40° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 25 months at 40° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 26 months at 40° C. and ≤65% relative humidity. In someaspects, the pharmaceutical composition is stable for 27 months at 40°C. and ≤65% relative humidity. In some aspects, the pharmaceuticalcomposition is stable for 28 months at 40° C. and ≤65% relativehumidity. In some aspects, the pharmaceutical composition is stable for29 months at 40° C. and ≤65% relative humidity. In some aspects, thepharmaceutical composition is stable for 30 months at 40° C. and ≤65%relative humidity. In some aspects, the pharmaceutical composition isstable for 36 months at 40° C. and 75% relative humidity.

Liquid and Powder Forms

In some aspects, the pharmaceutical composition of the presentdisclosure is a solution, an emulsion, or a suspension. In some aspects,the present disclosure provides for a concentrated form of losartan or apharmaceutically acceptable salt thereof, which can be combined with asuitable diluent to prepare a pharmaceutical composition describedherein. In some aspects, the concentrated form of losartan or apharmaceutically acceptable salt thereof is selected from the groupconsisting of: a powder, a plurality of granules, modified losartan, anda concentrated liquid form (e.g., a concentrated solution or alow-volume mixed solid and liquid phase). In some aspects, theconcentrated form of losartan or a pharmaceutically acceptable saltthereof can be combined with a suitable diluent to prepare one or moreof a solution, a suspension, and an emulsion.

In some aspects, the concentrated form of losartan or a pharmaceuticallyacceptable salt thereof is combined with the suitable diluent and heatedto form a pharmaceutically acceptable composition disclosed herein. Insome aspects, the concentrated form of losartan or a pharmaceuticallyacceptable salt thereof is combined with the suitable diluent and anadditional component to form a pharmaceutically acceptable compositiondisclosed herein. In some aspects, the additional component is a pHmodifying agent. In some aspects, the pH modifying agent is an acid. Insome aspects, the pH modifying agent is a base.

Solution

In some aspects, the pharmaceutical composition is a solution. In someaspects, the pharmaceutical composition is a solution and thepharmaceutical composition comprises losartan. In some aspects, thepharmaceutical composition is a solution and the pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of losartan. Insome aspects, the pharmaceutical composition is a solution and thepharmaceutical composition comprises losartan potassium.

In some aspects, the pharmaceutical composition is a solution comprisinglosartan substantially dissolved in a pharmaceutically acceptablevehicle. In some aspects, the solution comprises at least 50% oflosartan or pharmaceutically acceptable salt thereof in dissolved form.In some aspects, the solution comprises at least 55% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 60% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 65% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 70% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 75% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 80% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 85% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 90% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution comprises at least 95% of losartan orpharmaceutically acceptable salt thereof in dissolved form. In someaspects, the solution further comprises one or more inactive ingredientsselected from the group consisting of: co-solvents, pH modifying agents,surfactants, antioxidants, preservatives, and flavoring agents.

Emulsion

In some aspects, the pharmaceutical composition is an emulsion. In someaspects, the pharmaceutical composition is an emulsion and thepharmaceutical composition comprises losartan. In some aspects, thepharmaceutical composition is an emulsion and the pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of losartan. Insome aspects, the pharmaceutical composition is an emulsion and thepharmaceutical composition comprises losartan potassium.

In some aspects, the emulsion is a multiple emulsion. In some aspect,the emulsion is a microemulsion.

In some aspects, the emulsion comprises at least two immiscible liquidphases wherein one liquid phase is in the form of globules. In someaspects, the pharmaceutical composition comprises an emulsifying agent.In some aspects, the pharmaceutical composition is an emulsion wherein ahydrophobic phase comprises at least 50% of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition is an emulsion wherein a hydrophobic phasecomprises at least 60% of losartan or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition is an emulsionwherein a hydrophobic phase comprises at least 70% of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition is an emulsion wherein a hydrophobic phasecomprises at least 80% of losartan or a pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition is an emulsionwherein a hydrophobic phase comprises at least 90% of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition is an emulsion wherein a hydrophobic phasecomprises at least 95% of losartan or a pharmaceutically acceptable saltthereof.

Suspension

In some aspects, the pharmaceutical composition is a suspension. In someaspects, the pharmaceutical composition is a suspension and thepharmaceutical composition comprises losartan. In some aspects, thepharmaceutical composition is a suspension and the pharmaceuticalcomposition comprises a pharmaceutically acceptable salt of losartan. Insome aspects, the pharmaceutical composition is a suspension and thepharmaceutical composition comprises losartan potassium.

In some aspects, the suspension is a cloudy biphasic liquid comprising aplurality of losartan particles uniformly dispersed in apharmaceutically acceptable vehicle. In some aspects, at least 50% oflosartan or pharmaceutically acceptable salt thereof is in suspendedform. In some aspects, at least 60% of losartan or pharmaceuticallyacceptable salt thereof is in suspended form. In some aspects, at least70% of losartan or pharmaceutically acceptable salt thereof is insuspended form. In some aspects, at least 80% of losartan orpharmaceutically acceptable salt thereof is in suspended form. In someaspects, at least 90% of losartan or pharmaceutically acceptable saltthereof is in suspended form.

In some aspects, the suspension comprises a flocculating agent.

Powder

In some aspects, the present disclosure provides a powder which iscombined with a liquid to produce the pharmaceutical compositiondescribed herein.

In some aspects, the powder comprises losartan or a pharmaceuticallyacceptable form thereof. In some aspects, the powder comprises losartan.In some aspects, the powder comprises losartan potassium.

In some aspects, the powder comprises one or more pharmaceuticallyacceptable excipients.

In some aspects, the powder is bioequivalent to COZAAR®.

In some aspects, the powder is sterile.

In some aspects, the powder is non-pyrogenic.

In some aspects, the powder is substantially free of impurities.

In some aspects, the liquid is a solvent. In some aspects, the solventis water.

In some aspects, the liquid is provided in a container. In some aspects,the container is a bottle. In some aspects, the bottle is an amberbottle.

In some aspects, the container contains a suspending agent. In someaspects, the container contains a preservative. In some aspects, thecontainer contains a sweetener. In some aspects, the container containsa flavoring agent.

In some aspects, the powder is packaged in a sachet.

Granules

In some aspects, the present disclosure provides a plurality of granuleswhich is combined with a liquid to produce the pharmaceuticalcomposition described herein.

In some aspects, the plurality of granules comprises losartan or apharmaceutically acceptable salt thereof. In some aspects, the pluralityof granules comprises losartan. In some aspects, the plurality ofgranules comprises losartan potassium.

In some aspects, the plurality of granules comprises one or morepharmaceutically acceptable excipients.

In some aspects, the plurality of granules is bioequivalent to COZAAR®.

In some aspects, the plurality of granules is sterile.

In some aspects, the plurality of granules is non-pyrogenic.

In some aspects, the plurality of granules is substantially free ofimpurities.

In some aspects, the liquid is a solvent. In some aspects, the solventis water.

In some aspects, the liquid is provided in a container. In some aspects,the container is a bottle. In some aspects, the bottle is an amberbottle.

In some aspects, the container contains a suspending agent. In someaspects, the container contains a preservative. In some aspects, thecontainer contains a sweetener. In some aspects, the container containsa flavoring agent.

In some aspects, the plurality of granules is packaged in a sachet.

Particle Characterization

In some aspects, the suspension or the powder exhibits a dissolutionprofile as measured using a paddle type apparatus. In some aspects, thedissolution profile is measured at 50 rpm. In some aspects, thedissolution profile of the suspension or powder is measured in a mixtureof water and 0.1N HCl. In some aspects, less than 35% of the pluralityof losartan particles are dissolved in 15 minutes. In some aspects, lessthan 70% of the plurality of losartan particles are dissolved in 30minutes. In some aspects, at least 80% of the plurality of losartanparticles are dissolved in 60 minutes. In some aspects, at least 80% ofthe plurality of losartan particles are dissolved in 15 minutes. In someaspects, at least 85% of the plurality of losartan particles aredissolved in 15 minutes. In some aspects, at least 90% of the pluralityof losartan particles are dissolved in 15 minutes. In some aspects, atleast 95% of the plurality of losartan particles are dissolved in 15minutes. In some aspects, about 100% of the plurality of losartanparticles are dissolved in 15 minutes. In some aspects, at least 80% ofthe plurality of losartan particles are dissolved in 5 minutes. In someaspects, at least 85% of the plurality of losartan particles aredissolved in 5 minutes. In some aspects, at least 90% of the pluralityof losartan particles are dissolved in 5 minutes. In some aspects, atleast 95% of the plurality of losartan particles are dissolved in 5minutes. In some aspects, about 100% of the plurality of losartanparticles are dissolved in 5 minutes.

In some aspects, the suspension or powder exhibits a particle sizedistribution as measured using a particle size analyzer. In someaspects, the particle size analyzer is a Malvern Mastersizer particlesize analyzer. In some aspects, the particle size analyzer is a MalvernMastersizer 3000 particle size analyzer. In some aspects, the particlesize analyzer is a Malvern Zetasizer particle size analyzer.

In some aspects, the particle size distribution comprises a D10 valueless than 100 μm. In some aspects, the particle size distributioncomprises a D50 value less than 500 μm. In some aspects, the particlesize distribution comprises a D90 value less than 1000 μm. In someaspects, the particle size distribution comprises a D10 value less than100 μm, a D50 value less than 500 μm, and a D90 value less than 1000 μm.

In some aspects, the particle size distribution comprises a D10 valueless than 20 μm. In some aspects, the particle size distributioncomprises a D50 value less than 100 μm. In some aspects, the particlesize distribution comprises a D90 value less than 300 μm. In someaspects, the particle size distribution comprises a D10 value less than20 μm, a D50 value less than 100 μm, and a D90 value less than 300 μm.

In some aspects, the particle size distribution comprises a D10 valueless than 2 μm. In some aspects, the particle size distributioncomprises a D50 value less than 10 μm. In some aspects, the particlesize distribution comprises a D90 value less than 30 μm. In someaspects, the particle size distribution comprises a D10 value less than2 μm, a D50 value less than 10 μm, and a D90 value less than 30 μm.

In some aspects, the particle size distribution comprises a D10 valueless than 100 nm. In some aspects, the particle size distributioncomprises a D50 value less than 500 nm. In some aspects, the particlesize distribution comprises a D90 value less than 1000 nm. In someaspects, the particle size distribution comprises a D10 value less than100 nm, a D50 value less than 500 nm, and a D90 value less than 1000 nm.

In some aspects, the particle size distribution comprises a D10 valueless than or equal to 1 μm. In some aspects, the particle sizedistribution comprises a D50 value less than or equal to 5 μm. In someaspects, the particle size distribution comprises a D90 value less thanor equal to 15 μm. In some aspects, the particle size distributioncomprises a D10 value less than or equal to 1 μm, a D50 value less thanor equal to 5 μm, and a D90 value less than or equal to 15 μm.

In some aspects, the particle size distribution comprises a D90 valueless than 2 μm. In some aspects, the particle size distributioncomprises a D90 value less than 1 μm. In some aspects, the particle sizedistribution comprises a D90 value less than 500 nm.

In some aspects, the suspension or the powder has a sedimentation rateof less than 10% over a period of 24 hours. In some aspects, thesuspension or the powder has a sedimentation rate of less than 5% over aperiod of 24 hours.

Modified Losartan

In some aspects, the pharmaceutical composition comprises a modifiedlosartan. In some aspects, the powder comprises a modified losartan. Insome aspects, the modified losartan comprises losartan or apharmaceutically acceptable salt thereof complexed or coated with a wax,one or more polymers, or one or more other inactive ingredients. In someaspects, the modified losartan comprises losartan or a pharmaceuticallyacceptable salt thereof complexed or coated with a wax. In some aspects,the modified losartan comprises losartan or a pharmaceuticallyacceptable salt thereof complexed or coated with one or more polymers.In some aspects, the modified losartan is losartan or a pharmaceuticallyacceptable salt thereof coated with one or more inactive ingredients.

Crystalline Form

In some aspects, the powder or suspension comprises losartan or apharmaceutically acceptable salt thereof in crystalline form. In someaspects, the crystalline form is thermodynamically stable. In someaspects, the crystalline form is thermodynamically stable, as measuredby a substantially unchanged X-ray powder diffraction (XRPD) profilefollowing storage. In some aspects, the crystalline form isthermodynamically stable, as measured by a substantially unchangeddifferential scanning calorimetry (DSC) profile following storage.

Concentration of Losartan

In some aspects, the pharmaceutical composition comprises about 1 mg/mLto about 50 mg/mL of losartan or pharmaceutically acceptable saltthereof. In some aspects, the pharmaceutical composition comprises about2 mg/mL to about 20 mg/mL of losartan or a pharmaceutically acceptablesalt thereof. In some aspects, the pharmaceutical composition comprisesabout 5 mg/mL to about 20 mg/mL of losartan or a pharmaceuticallyacceptable salt thereof. In some aspects, the pharmaceutical compositioncomprises about 8 mg/mL to about 12 mg/mL of losartan or apharmaceutically acceptable salt thereof.

In some aspects, the pharmaceutical composition comprises about 1 mg/mLof losartan or a pharmaceutically acceptable salt thereof. In someaspects, the pharmaceutical composition comprises about 2 mg/mL oflosartan or a pharmaceutically acceptable salt thereof. In some aspects,the pharmaceutical composition comprises about 3 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 4 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 5 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 6 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 7 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 8 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 9 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 10 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 11 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 12 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 13 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 14 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 15 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 16 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 17 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 18 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 19 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 20 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 21 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 22 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 23 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 24 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 25 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 26 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 27 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 28 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 29 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 30 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 31 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 32 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 33 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 34 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 35 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 36 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 37 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 38 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 39 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 40 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 41 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 42 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 43 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 44 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 45 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 46 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 47 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 48 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 49 mg/mL of losartan or apharmaceutically acceptable salt thereof. In some aspects, thepharmaceutical composition comprises about 50 mg/mL of losartan or apharmaceutically acceptable salt thereof.

pH

In some aspects, the pharmaceutical composition has a pH between 2 and10. In some aspects, the pharmaceutical composition has a pH between 4and 7. In some aspects, the pharmaceutical composition has a pH between1 and 9. In some aspects, the pharmaceutical composition has a pHbetween 2 and 8. In some aspects, the pharmaceutical composition has apH between 3 and 7. In some aspects, the pharmaceutical composition hasa pH between 4 and 6. In some aspects, the pharmaceutical compositionhas a pH between 5 and 7. In some aspects, the pharmaceuticalcomposition has a pH between 3 and 5. In some aspects, thepharmaceutical composition has a pH between 7 and 9. In some aspects,the pH is 4.2.

In some aspects, the pharmaceutical composition has a pH less than 10.In some aspects, the pharmaceutical composition has a pH less than 9. Insome aspects, the pharmaceutical composition has a pH less than 8. Insome aspects, the pharmaceutical composition has a pH less than 7. Insome aspects, the pharmaceutical composition has a pH less than 6. Insome aspects, the pharmaceutical composition has a pH less than 5. Insome aspects, the pharmaceutical composition has a pH less than 4. Insome aspects, the pharmaceutical composition has a pH less than 3. Insome aspects, the pharmaceutical composition has a pH less than 2.

In some aspects, the pharmaceutical composition has a pH greater than10. In some aspects, the pharmaceutical composition has a pH greaterthan 9. In some aspects, the pharmaceutical composition has a pH greaterthan 8. In some aspects, the pharmaceutical composition has a pH greaterthan 7. In some aspects, the pharmaceutical composition has a pH greaterthan 6. In some aspects, the pharmaceutical composition has a pH greaterthan 5. In some aspects, the pharmaceutical composition has a pH greaterthan 4. In some aspects, the pharmaceutical composition has a pH greaterthan 3. In some aspects, the pharmaceutical composition has a pH greaterthan 2.

In some aspects, the pharmaceutical composition has a pH of about 2. Insome aspects, the pharmaceutical composition has a pH of about 2.5. Insome aspects, the pharmaceutical composition has a pH of about 3. Insome aspects, the pharmaceutical composition has a pH of about 3.5. Insome aspects, the pharmaceutical composition has a pH of about 4. Insome aspects, the pharmaceutical composition has a pH of about 4.1. Insome aspects, the pharmaceutical composition has a pH of about 4.2. Insome aspects, the pharmaceutical composition has a pH of about 4.3. Insome aspects, the pharmaceutical composition has a pH of about 4.4. Insome aspects, the pharmaceutical composition has a pH of about 4.5. Insome aspects, the pharmaceutical composition has a pH of about 5. Insome aspects, the pharmaceutical composition has a pH of about 5.5. Insome aspects, the pharmaceutical composition has a pH of about 6. Insome aspects, the pharmaceutical composition has a pH of about 6.5. Insome aspects, the pharmaceutical composition has a pH of about 7. Insome aspects, the pharmaceutical composition has a pH of about 7.5. Insome aspects, the pharmaceutical composition has a pH of about 8. Insome aspects, the pharmaceutical composition has a pH of about 8.5. Insome aspects, the pharmaceutical composition has a pH of about 9. Insome aspects, the pharmaceutical composition has a pH of about 9.5. Insome aspects, the pharmaceutical composition has a pH of about 10.

In some aspects, the pharmaceutical composition has a pH of 2. In someaspects, the pharmaceutical composition has a pH of 2.5. In someaspects, the pharmaceutical composition has a pH of 3. In some aspects,the pharmaceutical composition has a pH of 3.5. In some aspects, thepharmaceutical composition has a pH of 4. In some aspects, thepharmaceutical composition has a pH of 4.1. In some aspects, thepharmaceutical composition has a pH of 4.2. In some aspects, thepharmaceutical composition has a pH of 4.3. In some aspects, thepharmaceutical composition has a pH of 4.4. In some aspects, thepharmaceutical composition has a pH of 4.5. In some aspects, thepharmaceutical composition has a pH of 5. In some aspects, thepharmaceutical composition has a pH of 5.5. In some aspects, thepharmaceutical composition has a pH of 6. In some aspects, thepharmaceutical composition has a pH of 6.5. In some aspects, thepharmaceutical composition has a pH of 7. In some aspects, thepharmaceutical composition has a pH of 7.5. In some aspects, thepharmaceutical composition has a pH of 8. In some aspects, thepharmaceutical composition has a pH of 8.5. In some aspects, thepharmaceutical composition has a pH of 9. In some aspects, thepharmaceutical composition has a pH of 9.5. In some aspects, thepharmaceutical composition has a pH of 10.

Pharmacokinetic Parameters and Bioequivalence

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 98% to about 102% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 95% to about 105% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 90% to about 110% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 80% to about 125% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 75% to about 130% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 70% to about 135% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 65% to about 140% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 60% to about 145% of the mean T_(max) ofCOZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120% about 125%, about 130%, about 135%, about140%, or about 145% of the mean T_(max) of COZAAR®.

In some aspects, the mean T_(max) of the pharmaceutical compositiondescribed herein is about 50% to about 150% of the mean T_(max) ofCOZAAR®. In some aspects, the mean T_(max) of the pharmaceuticalcomposition described herein is about 40% to about 160% of the meanT_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 30% to about 170%of the mean T_(max) of COZAAR®. In some aspects, the mean T_(max) of thepharmaceutical composition described herein is about 20% to about 200%of the mean T_(max) of COZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 98% to about 102% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 95% to about 105% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 90% to about 110% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 80% to about 125% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 75% to about 130% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 70% to about 135% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 65% to about 140% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 60% to about 145% of the mean C_(max) ofCOZAAR®.

In some aspects, the mean C_(max) of the pharmaceutical compositiondescribed herein is about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120% about 125%, about 130%, about 135%, about140%, or about 145% of the mean C_(max) of COZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 98% to about 102% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 95% to about 105% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 90% to about 110% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 80% to about 125% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 75% to about 130% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 70% to about 135% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 65% to about 140% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 60% to about 145% of the mean AUC_(0-∞) ofCOZAAR®.

In some aspects, the mean AUC_(0-∞) of the pharmaceutical compositiondescribed herein is about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, about 105%, about110%, about 115%, about 120% about 125%, about 130%, about 135%, about140%, or about 145% of the mean AUC_(0-∞) of COZAAR®.

Additional Active Ingredients

In some aspects, the pharmaceutical composition comprises one or moreactive ingredients in addition to losartan or a pharmaceuticallyacceptable salt thereof. In some aspects, the one or more activeingredients are selected from the group consisting of: calcium channelblockers, diuretics, ACE inhibitors, and beta blockers. In some aspects,the one or more active ingredients are calcium channel blockers. In someaspects, the one or more active ingredients are diuretics. In someaspects, the one or more active ingredients are ACE inhibitors. In someaspects, the one or more active ingredients are beta blockers.

Viscosity

In some aspects, the pharmaceutical composition has a viscosity of lessthan 2000 centipoise, as measured using a Brookfield viscometer. In someaspects, the pharmaceutical composition has a viscosity of less than1000 centipoise, as measured using a Brookfield viscometer. In someaspects, the pharmaceutical composition has a viscosity of about 100 to2000 centipoise, as measured using a Brookfield viscometer. In someaspects, the pharmaceutical composition has a viscosity of about 100 to1500 centipoise, as measured using a Brookfield viscometer. In someaspects, the pharmaceutical composition has a viscosity of about 100 to1000 centipoise, as measured using a Brookfield viscometer. In someaspects, the pharmaceutical composition has a viscosity of about 500 to2000 centipoise, as measured using a Brookfield viscometer. In someaspects, the pharmaceutical composition has a viscosity of about 100 to2500 centipoise, as measured using a Brookfield viscometer.

Volume

In some aspects, the pharmaceutical composition is administered in avolume of 0.5 mL to 50 mL. In some aspects, the pharmaceuticalcomposition is administered in a volume of less than 100 mL. In someaspects, the pharmaceutical composition is administered in a volume ofless than 90 mL. In some aspects, the pharmaceutical composition isadministered in a volume of less than 80 mL. In some aspects, thepharmaceutical composition is administered in a volume of less than 70mL. In some aspects, the pharmaceutical composition is administered in avolume of less than 60 mL. In some aspects, the pharmaceuticalcomposition is administered in a volume of less than 50 mL. In someaspects, the pharmaceutical composition is administered in a volume ofless than 40 mL. In some aspects, the pharmaceutical composition isadministered in a volume of less than 30 mL. In some aspects, thepharmaceutical composition is administered in a volume of less than 20mL. In some aspects, the pharmaceutical composition is administered in avolume of less than 10 mL. In some aspects, the pharmaceuticalcomposition is administered in a volume of less than 5 mL.

In some aspects, the pharmaceutical composition is administered in avolume of about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about0.5 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL,about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 3 mL,about 3.5 mL, about 4 mL, about 4.5 mL, about 5 mL, about 5.5 mL, about6 mL, about 6.5 mL, about 7 mL, about 7.5 mL, about 8 mL, about 8.5 mL,about 9 mL, about 9.5 mL, or about 10 mL.

In some aspects, the pharmaceutical composition is administered in avolume of about 0.1 mL to about 20 mL, about 0.1 mL to about 15 mL,about 0.1 mL to about 10 mL, about 0.1 mL to about 2.5 mL, about 0.5 mLto about 2.5 mL, about 1 mL to about 10 mL, about 1 mL to about 2.5 mL,about 2 mL to about 10 mL, about 2 mL to about 3 mL, about 4 mL to about6 mL, or about 9 mL to about 11 mL. In some aspects, the pharmaceuticalcomposition is administered in a volume of about 2.5 mL to about 10 mL.

Container

In some aspects, a pharmaceutical composition is packaged in a glasscontainer. In some aspects, the powder is packaged in a glass container.In some aspects, the glass container is an amber glass container. Insome aspects, the amber glass container is child resistant. In someaspects, the amber glass container comprises a child resistant cap. Insome aspects, the pharmaceutical composition is packaged in a polymericcontainer. In some aspects, the polymeric container is child resistant.In some aspects, the polymeric container comprises a child resistantcap. In some aspects, the polymeric container comprises high densitypolyethylene (HDPE). In some aspects, the polymeric container compriseslow density polyethylene (LDPE).

Kit

In some aspects, the present disclosure provides for a kit comprising apharmaceutically acceptable composition described herein, and furthercomprising a set of instructions for administration of thepharmaceutically acceptable composition to a subject in need thereof. Insome aspects, the set of instructions comprises an instruction to add anamount of a diluent to a container comprising a concentrated form oflosartan or a pharmaceutically acceptable salt thereof, wherein the kitcomprises the container. In some aspects, the diluent is water.

In some aspects, the present disclosure provides for a kit comprising: aconcentrated form of losartan or a pharmaceutically acceptable saltthereof; a diluent; and a set of instructions, wherein the set ofinstructions comprises: instructions for combining the concentrated formof losartan or a pharmaceutically acceptable salt thereof and thediluent to form a pharmaceutically acceptable composition describedherein; and instructions for administration of the pharmaceuticallyacceptable composition to a subject in need thereof. In some aspects,the concentrated form of losartan is in the form of a powder or aplurality of granules. In some aspects, the concentrated form oflosartan or a pharmaceutically acceptable salt thereof is in the form ofa powder. In some aspects, the concentrated form of losartan or apharmaceutically acceptable salt thereof is in the form of a pluralityof granules.

In some aspects, the kit comprises a concentrated form of apharmaceutical composition disclosed herein. In some aspects, theconcentrated form is prepared by combining components of apharmaceutical composition disclosed herein without dilution to a finalconcentration suitable for administration to a subject. In some aspects,the concentrated form is a concentrated liquid form. In some aspects,the concentrated liquid form is a solution. In some aspects, theconcentrated liquid form is a suspension. In some aspects, theconcentrated form is a dry form. In some aspects, the dry form comprisesless than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% ofwater by weight of the dry form. In some aspects, the dry form is apowder or a plurality of granules.

Method of Preparing Suspension

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising combining a pluralityof losartan particles and a suspending agent. In some aspects, theplurality of losartan particles is combined with the suspending agent.

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising dissolving losartanor a pharmaceutically acceptable salt thereof in a suitable fluid (e.g.,water), adjusting the pH of the suitable liquid comprising losartan or apharmaceutically acceptable salt thereof, and combining the suitableliquid comprising losartan or a pharmaceutically acceptable salt thereofwith the remaining components of the suspension, thereby forming thesuspension.

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising combining losartan ora pharmaceutically acceptable salt thereof and one or more excipients,granulating the composition with a suitable fluid (e.g., water), dryingthe resulting composition to form a dry composition, and combining thedry composition with a suitable liquid, thereby forming the suspension.

In some aspects, the present disclosure provides a method of preparing asuspension described herein, the method comprising a step of particlesize reduction. In some aspects, the step of particle size reductioncomprises wet milling. In some aspects, the step of particle sizereduction comprises microfluidation. In some aspects, the step ofparticle size reduction comprises homogenization. In some aspects, thestep of particle size reduction comprises nano-milling.

In some aspects, a pH modifying agent is added after the plurality oflosartan particles is combined with the suspending agent. In someaspects, the pH modifying agent is selected from the group consistingof: citric acid, sodium citrate, acetic acid, sodium acetate, sodiumhydroxide, dibasic calcium phosphate, sodium dihydrogen phosphate, anddisodium hydrogen phosphate. In some aspects, the pH modifying agent isa buffer.

In some aspects, the one or more polymers are sprayed by dissolving theone or more polymers in a volatile solvent. In some aspects, thevolatile solvent is selected from the group consisting of: ethanol,acetone, or isopropyl alcohol. In some aspects, the volatile solvent isethanol. In some aspects, the volatile solvent is acetone. In someaspects, the volatile solvent is isopropyl alcohol.

In some aspects, heated air is added to cause evaporation of thevolatile solvent. In some aspects, evaporation of the volatile solventcauses deposition of the one or more polymers onto the surface of aparticle comprising losartan or a pharmaceutically acceptable saltthereof. In some aspects, the particles comprising losartan or apharmaceutically acceptable salt thereof are dried to form a modifiedlosartan. In some aspects, the plurality of losartan particles isprovided as a modified losartan which is preformed. In some aspects, theplurality of losartan particles comprises losartan or a pharmaceuticallyacceptable salt thereof.

In some aspects, the plurality of losartan particles are fluidized in afluidized bed system, and are then coated with one or more polymers. Insome aspects, the plurality of losartan particles comprises losartan ora pharmaceutically acceptable salt thereof. In some aspects, theplurality of losartan particles has a particle size of less than 1000μm. In some aspects, the plurality of losartan particles has a particlesize of less than 950 μm. In some aspects, the plurality of losartanparticles has a particle size of less than 900 μm. In some aspects, theplurality of losartan particles has a particle size of less than 850 μm.In some aspects, the plurality of losartan particles has a particle sizeof less than 800 μm. In some aspects, the plurality of losartanparticles has a particle size of less than 750 μm. In some aspects, theplurality of losartan particles has a particle size of less than 700 μm.In some aspects, the plurality of losartan particles has a particle sizeof less than 650 μm. In some aspects, the plurality of losartanparticles has a particle size of less than 600 μm. In some aspects, theplurality of losartan particles has a particle size of less than 550 μm.In some aspects, the plurality of losartan particles has a particle sizeof less than 500 μm. In some aspects, the plurality of losartanparticles has a particle size of less than 450 μm. In some aspects, theplurality of losartan particles has a particle size of less than 400 μm.In some aspects, the plurality of losartan particles has a particle sizeof less than 350 μm. In some aspects, the plurality of losartanparticles has a particle size of less than 300 μm. In some aspects, theplurality of losartan particles has a particle size of less than 250 μm.In some aspects, the plurality of losartan particles has a particle sizeof less than 200 μm. In some aspects, the plurality of losartanparticles has a particle size of less than 150 μm. In some aspects, theplurality of losartan particles has a particle size of less than 100 μm.In some aspects, the plurality of losartan particles has a particle sizeof less than 50 μm.

In some aspects, the one or more polymers comprise pH dependent polymers(e.g., Eudragit L, Eudragit S, or cellulose acetate phthalate) and/or pHindependent polymers (e.g., Eudragit RS, Eudragit RL, or celluloseacetate). In some aspects, the one or more polymers comprise pHdependent polymers (e.g., Eudragit L, Eudragit S, or cellulose acetatephthalate). In some aspects, the one or more polymers comprise EudragitL. In some aspects, the one or more polymers comprise Eudragit S. Insome aspects, the one or more polymers comprise cellulose acetatephthalate. In some aspects, the one or more polymers comprise pHindependent polymers (e.g., Eudragit RS, Eudragit RL, or celluloseacetate). In some aspects, the one or more polymers comprise EudragitRS. In some aspects, the one or more polymers comprise Eudragit RL. Insome aspects, the one or more polymers comprise cellulose acetate.

In some aspects, the modified losartan tastes less bitter than losartan.

In some aspects, the modified losartan is more stable than losartan.

Method of Preparing Solution or Emulsion

In some aspects, the present disclosure provides a method of preparing asolution or an emulsion described herein, comprising combining thecomponents of the solution or the emulsion.

In some aspects, losartan or a pharmaceutically acceptable salt thereofis dissolved in a hydrophobic phase (e.g., vegetable oil). In someaspects, an antioxidant is added to a hydrophobic phase. In someaspects, the hydrophobic phase comprising losartan or a pharmaceuticallyacceptable salt thereof is mixed with a hydrophilic phase. In someaspects, the hydrophilic phase comprises a sweetener. In some aspects,the hydrophilic phase comprises a flavoring agent. In some aspects, thehydrophilic phase comprises Polysorbate 80 and/or Tweens. In someaspects, the emulsion is prepared by combining and mixing thehydrophobic phase and the hydrophilic phase. In some aspects, thehydrophobic phase and hydrophilic phase are mixed at a high speed usinga homogenizer.

Method of Preparing Powder

In some aspects, the present disclosure provides a method of preparing apowder, the method comprising dry blending the components of apharmaceutical composition described herein. In some aspects, thepharmaceutical composition is a suspension described herein.

Method of Preparing Modified Losartan

In some aspects, the present disclosure provides a method of preparingmodified losartan, the method comprising complexing or coating losartanor a pharmaceutically acceptable salt thereof with a substance, whereinthe substance is a wax, a polymer, or one or more other inactiveingredients. In some aspects, the modified losartan is formed duringpreparation of the pharmaceutical composition. In some aspects, modifiedlosartan is formed by complexation with an ion exchange resin. In someaspects, modified losartan is formed by complexation with acyclodextrin. In some aspects, the modified losartan is prepared bymicroencapsulation of losartan or a pharmaceutically acceptable saltthereof in a coat of inactive ingredients.

Method of Treatment

In some aspects, the present disclosure provides a method of treating asubject in need thereof comprising administering to the subject atherapeutically effective amount of the pharmaceutical compositiondescribed herein.

In some aspects, the present disclosure provides a method of treatinghypertension in a subject in need thereof comprising administering tothe subject a therapeutically effective amount of the pharmaceuticalcomposition described herein. In some aspects, the present disclosureprovides a method of treating adult hypertension in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of the pharmaceutical composition described herein. Insome aspects, the present disclosure provides a method of treatingpediatric hypertension in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of thepharmaceutical composition described herein. In some aspects, thepresent disclosure provides a method of treating hypertension in asubject in need thereof comprising administering to the subject atherapeutically effective amount of the pharmaceutical compositiondescribed herein wherein the subject is a patient with left ventricularhypertrophy. In some aspects, the present disclosure provides a methodof treating nephropathy in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of thepharmaceutical composition described herein. In some aspects, thepresent disclosure provides a method of treating nephropathy in asubject in need thereof comprising administering to the subject atherapeutically effective amount of the pharmaceutical compositiondescribed herein wherein the subject is a patient with type 2 diabetes.

In some aspects, the subject has been diagnosed with pre-hypertension orhypertension. In some aspects, the subject has been diagnosed withpre-hypertension. In some aspects, the subject has been diagnosed withhypertension. In some aspects, the subject has a history ofhypertension.

In some aspects, the subject has been diagnosed with left ventricularhypertrophy. In some aspects, the subject has been diagnosed with bothhypertension and left ventricular hypertrophy.

In some aspects, the subject has been diagnosed with type 2 diabetes.

In some aspects, the subject has been diagnosed with nephropathy.

In some aspects, the subject has been diagnosed with diabeticnephropathy.

In some aspects, the subject has been diagnosed with proteinuria.

In some aspects, the subject exhibits a urinary albumin to creatinineratio of greater than or equal to 300 mg/g.

In some aspects, the subject has been diagnosed with an elevated serumcreatinine.

In some aspects, the pharmaceutical composition is co-administered withat least one other pharmaceutical agent. In some aspects, the at leastone pharmaceutical agent is an antihypertensive agent. In some aspects,the antihypertensive agent is selected from the group consisting of: anangiotensin II antagonist, an angiotensin converting enzyme inhibitor,or a neutral endopeptidase/angiotensin converting enzyme inhibitor. Insome aspects, the antihypertensive agent is an angiotensin IIantagonist. In some aspects, the antihypertensive agent is anangiotensin converting enzyme inhibitor. In some aspects, theantihypertensive agent is a neutral endopeptidase/angiotensin convertingenzyme inhibitor.

Having described the invention with reference to the different aspectsof the invention, other aspects will become apparent to one skilled inthe art from consideration of the specification.

The innovation is further defined by reference to the followingexamples. It will be apparent to those skilled in the art that manymodifications to the composition may be practiced without departing fromthe scope of this invention.

EXAMPLES

In non-limiting examples, pharmaceutical compositions of losartan andmethods of producing the same are disclosed herein. Examples 1, 2, 6,and 13 and the Tables 1, 2, 5, and 12 therein shows alternatives forformulation of an oral suspension of losartan. Example 3 provides amethod of producing the oral suspension of Example 2, and Example 14provides a method of producing the suspension of Example 13. Examples 4,5, and 10-12, and Tables 3, 4, and 9-11 therein provide oral liquidsolutions of losartan. Examples 7-9 and Tables 6-8 therein providepowder compositions suitable for reconstitution to prepare a solution(Example 7 and 8) or a suspension (Example 9).

Example 1: Suspension 1

A suspension of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 1 Losartan Suspension for Oral Administration Losartan PotassiumOral Suspension, 10 mg/mL INGREDIENT Composition Qty/100 mL purifiedwater, USP 80-100 g methylparaben, NF 0.1-0.3 g propylparaben, NF0.01-0.03 g losartan potassium, USP 0.5-1.5 g hydroxy ethyl cellulose1-1.4 g (NATROSOL ™ 250 L), NF Xanthan gum, NF (XANTURAL ® 180) 0.5-1.5g microcrystalline cellulose and 1-2 g carboxymethylcellulose sodium, NF(AVICEL ® RC-591) disodium edetate, NF 0.1-0.2 g simethicone emulsion30%, USP (Q7- 0.8-1.2 g 2587 simethicone emulsion 30%, USP) a flavoringagent 5-15 mg sucralose micronized, NF (SPLENDA ®) 0.2-0.6 g anhydrouscitric acid, USP Qs to desired pH (5% citric acid solution in purifiedwater)

Example 2: Suspension 2

A suspension of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 2 Losartan Suspension for Oral Administration Losartan PotassiumOral Suspension, 10 mg/mL Composition ITEM Qty/100 mL NO. INGREDIENTpH-4.2 pH-5.0 1 purified water, USP 80-100 g 80-100 g 2 methylparaben,NF 0.1-0.3 g 0.18 g 3 propylparaben, NF 0.02 g 0.02 g 4 losartanpotassium, USP 1.000 g 1.000 g 5 hydroxyethyl cellulose 1.20 g 1.20 g(NATROSOL ™ 250 L), NF 6 Xanthan gum, NF (XANTURAL ® 180) 0.10 g 0.10 g7 microcrystalline cellulose and 1.50 g 1.50 g carboxymethylcellulosesodium, NF (AVICEL ® RC-591) 8 disodium edetate, NF 0.15 g 0.15 g 9simethicone emulsion 30%, USP 1.00 g 1.00 g (Q7-2587 simethiconeemulsion 30%, USP) 10 sucralose micronized, NF (SPLENDA ®) 0.40 g 0.40 g11 anhydrous citric acid, USP Qs to adjust pH (5% citric acid solutionwith purified water) 12 flavoring agent 5-15 mg

Example 3: Method of Producing Suspension of Example 2

-   -   1. Preservatives (methylparaben, NF and propylparaben, NF) were        dissolved in purified water at a temperature 80-85° C. Once        dissolved, the content was cooled to 25° C.    -   2. Losartan (losartan potassium, USP) was added to the above        solution once the temperature was between 25-30° C. and the drug        was dissolved in water with preservatives.    -   3. A 5% citric acid solution was added with continuous        homogenizing in an amount such that the final pH of the        composition after all components were added would be the desired        pH (here, either 4.2 or 5.0).    -   4. The viscosity modifying agents/thickening agents/suspending        agents (hydroxyethyl cellulose (NATROSOL™ 250 L), NF and xanthan        gum, NF (XANTURAL® 180)) were added to the composition of step 2        using high shear mixing.    -   5. Disodium edetate and simethicone emulsion 30% were added to        the composition of step 4.    -   6. Sweetener was added and the composition was mixed for a few        minutes.    -   7. A flavoring agent was added.    -   8. Qs to batch volume with purified water and composition was        mixed.

In some aspects, the pH modifying agent (here, citric acid in step 3) isadded after any other step.

Example 4: Losartan Solution

A solution of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 3 Losartan Solution for Oral Administration Losartan PotassiumOral Solution, 10 mg/mL ITEM Composition NO. INGREDIENTS Qty/100 mL 1purified water, USP 90.00 g 90.00 g 2 methylparaben, NF  0.18 g  0.18 g3 propylparaben, NF  0.02 g  0.02 g 4 losartan potassium, USP 1.000 g1.000 g 5 hydroxyethyl cellulose  1.20 g  1.20 g (NATROSOL ™ 250 L), NF8 disodium edetate, NF  0.15 g  0.15 g 10 sucralose micronized, (NFSPLENDA ®)  0.40 g  0.40 g 11 NaOH Qs to adjust pH > 6

Losartan Potassium was dissolved in water and mixed with the rest of theingredients. The pH was adjusted to 6 using a Sodium Hydroxide solution.

Example 5: Losartan Solution

A solution of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 4 Losartan solution for oral administration Formula Quantity NoIngredients (g/100 mL) 1. Polyethylene Glycol 400, NF  2.5 g 2.Propylene glycol, USP  2.5 g 3. Methylparaben, NF  0.18 g 4.Propylparaben, NF  0.02 g 5. Sodium Phosphate, Monobasic USP 0.114 g 6.Sodium Phosphate, Dibasic USP 0.144 g 7. Losartan Potassium, USP  1.00 g8. Povidone, NF (Kollidon 90F)  1.00 g 9. Hypromellose 2910, USP  2.0 g(Methocel E50 Premium UV) 10. Xanthan gum, NF  0.10 g 11. Purified WaterUSP QS

Polyethylene glycol and Propylene Glycol were mixed, and Methylparabenand Propyl Paraben were added to the mixture to make the preservativephase. Phosphate buffer was prepared using Monobasic and Dibasic SodiumPhosphate. Losartan Potassium was dissolved in water. The preservativephase and buffer phase (monobasic and dibasic sodium phosphate) werethen added to make a clear solution. The remaining Ingredients wereadded with constant mixing using a homogenizer.

Example 6: Losartan Suspension

A suspension of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 5 Losartan suspension for oral administration: Quantity NoIngredients (g/100 mL) 1. Polyethylene Glycol 400, NF  2.5 g 2.Propylene glycol, USP  2.5 g 3. Methylparaben, NF 0.18 g 4.Propylparaben, NF 0.02 g 5. Anhydrous Citric Acid, USP  5.0 g 6. VitaminE Polyethylene Glycol Succinate, NF  2.0 g 7. Losartan Potassium, USP1.00 g 8. Povidone, NF (Kollidon 90F)  1.0 g 9. Hypromellose 2910, USP(Methocel E50 Premium LV)  1.0 g 10. Microcrystalline Cellulose &Carboxymethylcellulose  1.0 g Sodium, NF (Avicel RC-591) 11. SimethiconeEmulsion, USP 30%  1.0 g 12. Purified Water USP QS

-   -   Polyethylene glycol and Propylene Glycol were mixed, and        Methylparaben and Propyl Paraben were added to the mixture.    -   Phosphate buffer was prepared using Monobasic and Dibasic Sodium        Phosphate.    -   Citric acid was added to water to a 5% final concentration.    -   Losartan Potassium was dissolved in water. The 5% citric acid        solution was added to dissolve a portion of the API and adjust        pH to 4.2.    -   The preservative phase and buffer phase were added.    -   The remaining Ingredients were added with constant mixing using        a homogenizer. Citric acid was used to adjust the solution to a        final pH of 4.2.

Example 7: Losartan Powder for Solution

A solution of losartan suitable for oral administration was preparedfrom a composition having ingredients in the following proportions:

TABLE 6 Losartan solution for oral administration Sr. # Ingredients %w/w gm/100 ml 1 Losartan Potassium 33.33 1 2 Sodium Benzoate 1.67 0.05 3Sodium Citrate 3.33 0.1 4 Xanthan Gum 1.67 0.05 6 Citric acid 1.67 0.057 Sucralose 1.67 0.05 8 Sorbitol 56.67 1.7

Ingredients 1-8 were mixed, then passed through a sieve having a meshsize of 20 (“20 #”), and further mixed using a blender. The resultingmixture can be combined with a suitable diluent to prepare a solutionwith is administrable as a pharmaceutical composition.

Example 8: Losartan Powder for Solution

A solution of losartan suitable for oral administration was preparedfrom a composition having ingredients in the following proportions:

TABLE 7 Losartan solution for oral administration Sr.# Ingredients % w/wgm/100 ml 1 Losartan Potassium 33.33 1 2 Potassium sorbate 1.00 0.03 4Xanthan Gum 1.67 0.05 6 Dibasic Sodium/Calcium phosphate 1.67 0.05 7Sucralose 1.00 0.03 8 Sorbitol 61.33 1.84

Ingredients 1-8 were mixed, then passed through a 20 #sieve, and furthermixed using a blender. The resulting mixture can be combined with asuitable diluent to prepare a solution with is administrable as apharmaceutical composition.

Example 9: Losartan Powder for Suspension

A suspension of losartan suitable for oral administration was preparedfrom a composition having ingredients in the following proportions:

TABLE 8 Losartan Powder for oral administration Sr. # Ingredients mg 1Losartan Potassium 100 2 Microcrystalline Cellulose 105 3 LactoseMonohydrate 51 4 Pregelatinized Starch 1500 41.9 5 magnesium Stearate2.1 6 Citric Acid 0.75 7 Sodium Citrate 1 8 Sucralose 0.5 9 Sorbitol97.75 10 Xanthum gum 5

Ingredients 1-10 were mixed and passed through a 20 #sieve, then furthermixed using a rapid granulator. The powder mix was granulated with waterand allowed to dry until the LOD was below 1%. The resulting mixture canbe combined with a suitable diluent or suspending agent to prepare asuspension with is administrable as a pharmaceutical composition. Forexample, 40.5 mg of the mixture, which contains 10 mg of losartan, canbe reconstituted in water to prepare a suitable dosage form.

Example 10: Losartan Solution

A solution of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 9 Losartan solution for oral administration Sr. # Ingredients %w/w gm/100 ml 1 Losartan Potassium 2.35 1 2 Sodium Benzoate 0.47 0.2 3Glycerine 94.71 40.25 4 Xanthan Gum 0.59 0.25 5 PVKK30 0.71 0.3 6Sucralose 1.18 0.5

Losartan Potassium was dissolved in water, and the remaining excipientswere added with constant stirring using a homogenizer.

Example 11: Losartan Solution

A solution of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 10 Losartan solution for oral administration Sr. # Ingredientg/1000 mL 1 Losartan Potassium, USP  10 g 2 PEG 400  25 g 3 PropyleneGlycol  25 g 4 Monobasic sodium phosphate 0.57 (anhydrous) 5 Dibasicsodium phosphate 0.72 (dried) 6 Methyl Paraben 1.8 g 7 Propyl Paraben0.2 g 8 Purified Water QS to 1000 mL

Polyethylene glycol and Propylene Glycol were mixed, and Methylparabenand Propyl Paraben were added to the mixture to make the preservativephase. Phosphate buffer was prepared using Monobasic and Dibasic SodiumPhosphate. Losartan Potassium was dissolved in water. The preservativephase and buffer phase (monobasic and dibasic sodium phosphate) werethen added to make a clear solution. Add purified water to total volume.

Example 12: Losartan Solution

A solution of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 11 Losartan solution for oral administration Sr.# Ingredientg/1000 mL 1 Losartan Potassium, USP  10 g 2 Monobasic sodium phosphate0.57 (anhydrous) 3 Dibasic sodium phosphate 0.72 (dried) 4 MethylParaben 1.8 g 5 Propyl Paraben 0.2 g 6 Water q.s. to 1000 ml

-   -   Preservatives (methylparaben, NF and propylparaben, NF) were        dissolved in purified water at a temperature 80-85° C. Once        dissolved, the content was cooled to 25° C.    -   Losartan (losartan potassium, USP) was added to the above        solution once the temperature was between 25-30° C. and the drug        was dissolved in water with preservatives.    -   Phosphate buffer was prepared using Monobasic and Dibasic Sodium        Phosphate and added to the above solution.    -   Add purified water to total volume.

Example 13: Losartan Suspension

A suspension of losartan suitable for oral administration was preparedhaving ingredients in the following proportions:

TABLE 12 Losartan suspension for oral administration Ingredient Per 100mL Losartan Potassium, USP  1.00 g Methylparaben, NF  0.18 gPropylparaben, NF  0.02 g Purified Water, USP (q.s.) 85.00 g + q.s.Hydroxyethyl cellulose, NF (Natrosol  1.2 g 250 L Pharm) Xanthan Gum, NF(Xantural 180)  0.10 g Microcrystalline Cellulose and Carboxymethyl  1.5g cellulose Sodium, NF (Avicel RC-591) Edetate Disodium, USP  0.15 gSimethicone Emulsion 30% USP (Q7-2587  1.00 g Simethicone Emulsion 30%USP) Sucralose, NF (Splenda ®, Micronized  0.40 g (Powder) MonobasicSodium phosphate (anhydrous) 0.114 g Disodium Phosphate (dried) 0.144 g

Example 14: Method of Producing Suspension of Example 13

-   -   Preservatives (methylparaben, NF and propylparaben, NF) were        dissolved in purified water at a temperature 80-85° C. Once        dissolved, the content was cooled to 25° C.    -   Losartan (losartan potassium, USP) was added to the above        solution once the temperature was between 25-30° C. and the drug        was dissolved in water with preservatives.    -   Phosphate buffer was prepared using Monobasic and Dibasic Sodium        Phosphate and added to the above solution.    -   The viscosity modifying agents/thickening agents/suspending        agents (hydroxyethyl cellulose (NATROSOL™ 250 L), NF and xanthan        gum, NF (XANTURAL® 180)) were added to the composition of step 2        using high shear mixing.    -   Disodium edetate and simethicone emulsion 30% were added to the        composition of step 4.    -   Sweetener was added and the composition was mixed for a few        minutes.    -   Qs to batch volume with purified water and composition was        mixed.

Example 15: Analysis of Losartan Formulations Administered to Rabbits

60 male New Zealand white rabbits were split into Groups 1 to 6 of 10random rabbits each.

5 mg of losartan potassium was administered orally to Group 1 as theformulation of Example 11 (a solution).

5 mg of losartan potassium was administered orally to Group 2 as theformulation of Example 12 (a solution).

5 mg of losartan potassium was administered orally to Group 3 as theformulation of Example 6 (a suspension).

5 mg of losartan potassium was administered orally to Group 4 as theformulation of Example 2 (a suspension).

5 mg of losartan potassium was administered orally to Group 5 as theformulation of Example 13 (a suspension).

5 mg of losartan potassium was administered orally to Group 6 as asuspension of COZAAR® prepared according to the instructions provided inCOZAAR® label.

The plasma concentration of losartan over time following administrationis depicted in FIG. 1 . The plasma concentration of losartan carboxylicacid over time following administration is depicted in FIG. 2 . Losartancarboxylic acid is a losartan metabolite. FIG. 1 demonstrates that allthe administered formulations provide a therapeutically effectiveconcentration of losartan over a period of at least ten hours. Multipletest formulations have a comparable C_(max) and AUC to that of theCOZAAR® suspension.

Pharmacokinetic parameters for losartan are presented in Table 13 foreach of the Groups 1 to 6. Average values are presented.

TABLE 13 Losartan Pharmacokinetic Parameters Group 6 (compounded Group 1Group 2 Group 3 Group 4 Group 5 suspension; (solution) (solution)(suspension) (suspension) (suspension) COZAAR ®) C_(max) (ng/ml) 181.05173.73 212.11 93.78 57.03 205.76 AUC_(0-24 hr) 630.43 539.14 772.02577.95 401.31 712.05 (ng · h/ml) AUC_(0-∞) 763.32 682.8 976.0 902.8528.7 880.5 (ng · h/ml) T_(max) (h) 0.17 2.5 2.35 4 4 2 T_(1/2) (h) 4.533.51 4.81 5.58 5.23 3.41

The formulations of Groups 1 and 3 resulted in a C_(max) and anAUC_(0-∞) between about 80% to about 125% of the C_(max) and anAUC_(0-∞) for COZAAR® compounded suspension (Group 6). The formulationof Group 2 resulted in a C_(max) between about 80% to about 125% of theC_(max) of COZAAR® suspension but an AUC_(0-∞) less than 80% of theAUC_(0-∞) of COZAAR® suspension. The formulation of Group 4 resulted inan AUC_(0-∞) between about 80% to about 125% of the AUC_(0-∞) of COZAAR®suspension, but an C_(max) less than 80% of the C_(max) of COZAAR®suspension. The formulation of Group 5 resulted in a C_(max) and anAUC_(0-∞) below 80% of the C_(max) and an AUC_(0-∞) for COZAAR®suspension.

TABLE 14 Losartan Carboxylic Acid Pharmacokinetic ParametersPharmacokinetic parameters for losartan carboxylic acid are presented inTable 14 for each of the Groups 1 to 6. Average values are presented.Group 6 (compounded Group 1 Group 2 Group 3 Group 4 Group 5 suspension;(solution) (solution) (suspension) (suspension) (suspension) COZAAR ®)C_(max) (ng/ml) 39.17 23.65 45.60 34.86 32.88 50.76 AUC_(0-24 hr) 267.27162.73 250.30 209.43 245.43 278.64 (ng · h/ml) T_(max) (h) 4 4 3.5 4 6 4

The data demonstrates that the test formulations of Groups 1-5 result inthe pharmacokinetic profile of losartan metabolite comparable to that ofCOZAAR® suspension (Group 6).

Example 16: Dissolution, Impurity, and Stability Analysis for theFormulation of Group 4

The formulation of Group 4 was tested for the presence of losartanImpurity D and losartan Impurity E under various conditions. As used inthe Examples herein, “ACC” refers to accelerated conditions, in whichthe formulation was placed at 40° C. and 75% relative humidity (RH).“INT” refers to intermediate conditions, in which the formulation isplaced at 30° C. and 65% RH. “CRT” refers to controlled roomtemperature, in which the formulation is placed at 25° C. and 60% RH.

TABLE 15 Analysis of the Formulation of Group 4 Under Various Conditions1 Month 1 Month 1 Month 2 Month 2 Month Test Initial ACC IRT CRT INT ACCAssay for 100.3%  99.8%  99.8% 99.4%  99.9% 100.2 Losartan PotassiumRelated Substances: Impurity D ND ND ND ND ND ND Impurity E ND ND ND NDND ND Dissolution 102.8% 100.6% 100.1% 99.7% 101.5% 102.0% in 30 minsND: None detected

As Table 15 shows, the formulation of Group 4 retained over 99% oflosartan potassium over all conditions tested, indicating purity andstability of the formulation. No Impurity D or Impurity E were detectedunder any of the conditions tested, further indicating both purity andstability of the losartan formulation. The same dissolution profile wasobserved in all conditions, further demonstrating stability. No colorchange was observed over time, further indicating purity and stability.

Example 17: Impurity and Stability Analysis for the Formulation of Group5

The formulation of Group 5 was tested for the presence of losartanImpurity D and losartan Impurity E under various conditions. Data arepresented as wt/wt % relative to the theoretical initial amount oflosartan potassium, which corresponds to about 10 mg/mL losartan.

TABLE 16 Analysis of the Formulation of Group 5 Under Various Conditions20 days 1 Month 3 Month 3 Month Test Initial CRT CRT CRT ACC Assay forlosartan 102.1% 98.7 97.6 102.3 98 potassium Losartan Impurity ND ND NDND ND D Losartan Impurity ND ND ND ND 0.07 E ND: None detected

As Table 16 shows, the formulation of Group 5 retained at least 98% oflosartan under all conditions tested, indicating stability and purity.Impurity D was not detectable and Impurity E was less than 0.1% wt/wtunder all conditions tested, further indicating stability and purity.

Example 18: Impurity and Stability Analysis for the Formulation ofExample 5

The formulation of Example 5 was tested for the presence of losartanImpurity D and losartan Impurity E under various conditions. Data arepresented as wt/wt % relative to the theoretical initial amount oflosartan potassium.

TABLE 17 Analysis of the Formulation Example 5 Under Various ConditionsTest Initial 48 days CRT Assay for losartan 99.50% 99.90% potassiumLosartan Impurity D ND ND Losartan Impurity E ND ND ND: None detected

As Table 17 shows, the formulation of Example 5 retained over 99% oflosartan under all conditions tested, indicating stability and purity.Impurity D was not detectable and Impurity E was less than the limits ofquantification after 48 days at room temperature, further indicatingstability and purity.

1-123. (canceled)
 124. An oral pharmaceutical composition comprising:about 1 mg/mL to about 50 mg/mL of losartan or a pharmaceuticallyacceptable salt thereof, about 0.5 mg/mL to about 1.5 mg/mL of asuspending agent, about 0.5 mg/mL to about 1.5 mg/mL of a pH modifyingagent, about 5 mg/mL to about 15 mg/mL of a crystallization inhibitor,about 0.1 mg/mL to about 3 mg/mL of a preservative, about 1 mg/mL toabout 10 mg/mL of an antifoaming agent, about 20 mg/mL to about 60 mg/mLof a solubilizer, and wherein the pharmaceutical composition is asuspension that is bioequivalent to COZAAR®.
 125. The oralpharmaceutical composition of claim 124, further comprising one or morepharmaceutically acceptable excipients selected from the groupconsisting of an emulsifying agent, an antioxidant, a chelating agent, asurfactant or wetting agent, a sweetener, a stabilizer, a flavoringagent, and a colorant.
 126. The oral pharmaceutical composition of claim124, wherein the suspending agent is selected from the group consistingof hydroxyethylcellulose, methylcellulose, hydroxymethylcellulose,hydroxypropylmethylcellulose, microcrystalline cellulose, sodiumcarboxymethylcellulose, xanthan gum, acacia, an alginate, and guar gum,or a combination thereof.
 127. The oral pharmaceutical composition ofclaim 124 substantially free of one or more impurities.
 128. The oralpharmaceutical composition of claim 127, wherein the one or moreimpurities comprises less than 5 wt/wt % of all impurities relative tothe weight of losartan in the pharmaceutical composition, and comprisesone or more of: a product of losartan oxidation, a product of losartandegradation, a side product of a method of losartan synthesis, abyproduct of a method of losartan synthesis, losartan carboxylic acid,losartan impurity D, and losartan impurity E.
 129. The oralpharmaceutical composition of claim 124, wherein the composition isstable after storage for at least 12 months as measured by one or moresubstantially unchanged characteristics after storage selected from thegroup consisting of: the concentration of losartan in the pharmaceuticalcomposition; the concentration of an impurity in the pharmaceuticalcomposition; the visual appearance of the pharmaceutical composition;the viscosity of the pharmaceutical composition; the uniformity of thepharmaceutical composition; and the sedimentation rate of thepharmaceutical composition.
 130. The oral pharmaceutical composition ofclaim 129, wherein the pharmaceutical composition is stable at: 15°C.-25° C. and ≤65% relative humidity, or 30° C. and ≤65% relativehumidity, or 40° C. and 75% relative humidity.
 131. The oralpharmaceutical composition of claim 124, comprising about 10 mg/mL oflosartan or a pharmaceutically acceptable salt thereof.
 132. The oralpharmaceutical composition of claim 124, wherein the pharmaceuticallyacceptable salt is losartan potassium.
 133. The oral pharmaceuticalcomposition of claim 124, having a pH between 4 and
 8. 134. The oralpharmaceutical composition of claim 124, wherein the mean C_(max) isabout 98% to about 102%, about 95% to about 105%, about 90% to about110%, or about 80% to about 125% of the mean C_(max) of COZAAR®. 135.The oral pharmaceutical composition of claim 124, wherein the meanAUC_(0-∞) is about 98% to about 102%, about 95% to about 105%, about 90%to about 110%, or about 80% to about 125% of the mean AUC_(0-∞) ofCOZAAR®.
 136. An oral pharmaceutical composition comprising: about 1mg/mL to about 50 mg/mL of losartan or a pharmaceutically acceptablesalt thereof, about 0.5 mg/mL to about 1.5 mg/mL of a suspending agent,about 0.5 mg/mL to about 1.5 mg/mL of a pH modifying agent, about 5mg/mL to about 15 mg/mL of a crystallization inhibitor, about 0.1 mg/mLto about 3 mg/mL of a preservative, about 1 mg/mL to about 10 mg/mL ofan antifoaming agent, about 20 mg/mL to about 60 mg/mL of a solubilizer,and wherein the pharmaceutical composition is a suspension.
 137. Theoral pharmaceutical composition of claim 136, comprising one or morepharmaceutically acceptable excipients selected from the groupconsisting of an emulsifying agent, an antioxidant, a chelating agent, asurfactant or wetting agent, a sweetener, a stabilizer, a flavoringagent, and a colorant.
 138. The oral pharmaceutical composition of claim124, further comprising PEG 400, propylene glycol, or both.
 139. Theoral pharmaceutical composition of claim 124, the preservativecomprising methyl paraben, propyl paraben, or both.
 140. The oralpharmaceutical composition of claim 124, the pH modifying agentcomprising sodium phosphate monobasic, sodium phosphate dibasic, orboth.
 141. The oral pharmaceutical composition of claim 124, theflavoring agent comprising a mint flavor.
 142. The oral pharmaceuticalcomposition of claim 124, comprising about 20 mg/mL to about 30 mg/mLPEG 400 and/or about 20 mg/mL to about 30 mg/mL propylene glycol, about0.3 mg/mL to about 1.2 mg/mL sodium phosphate monobasic and/or about 0.5mg/mL to about 1.5 mg/mL sodium phosphate dibasic, and a mint flavor inan amount less than 10 wt/wt %.
 143. The oral pharmaceutical compositionof claim 124, the crystallization inhibitor comprisingpolyvinylpyrrolidone K90.
 144. The oral pharmaceutical composition ofclaim 124, the suspending agent comprising xanthan gum.
 145. The oralpharmaceutical composition of claim 124, further comprising simethiconeemulsion.
 146. The oral pharmaceutical composition of claim 124,comprising about 10 mg/mL to about 20 mg/mL polyvinylpyrrolidone K90,about 1 mg/mL to about 2.5 mg/mL xanthan gum, about 5 mg/mL to about 10mg/mL simethicone emulsion, and sucralose in an amount less than 10wt/wt %.
 147. A method of treating a disease or condition responsive toangiotensin II receptor inhibition in a human subject comprisingadministering to the subject a therapeutically effective amount of anoral pharmaceutical composition comprising: about 1 mg/mL to about 50mg/mL of losartan or a pharmaceutically acceptable salt thereof, about0.5 mg/mL to about 1.5 mg/mL of a suspending agent, about 0.5 mg/mL toabout 1.5 mg/mL of a pH modifying agent, about 5 mg/mL to about 15 mg/mLof a crystallization inhibitor, about 0.1 mg/mL to about 3 mg/mL of apreservative, about 1 mg/mL to about 10 mg/mL of an antifoaming agent,about 20 mg/mL to about 60 mg/mL of a solubilizer, and wherein thepharmaceutical composition is a suspension.
 148. The method of claim138, wherein the subject has one or more of pre-hypertension,hypertension, left ventricular hypertrophy, type 2 diabetes,nephropathy, diabetic nephropathy, proteinuria, and elevated serumcreatinine.
 149. The method of claim 138, wherein the pharmaceuticalcomposition is bioequivalent to COZAAR®.
 150. The method of claim 147,wherein the pharmaceutical composition is substantially free of one ormore impurities.
 151. The method of claim 150, wherein the one or moreimpurities comprises less than 5 wt/wt % of all impurities relative tothe weight of losartan in the pharmaceutical composition, and comprisesone or more of: a product of losartan oxidation, a product of losartandegradation, a side product of a method of losartan synthesis, abyproduct of a method of losartan synthesis, losartan carboxylic acid,losartan impurity D, and losartan impurity E.
 152. The method of claim147, wherein the pharmaceutical composition is stable after storage forat least 12 months as measured by one or more substantially unchangedcharacteristics after storage selected from the group consisting of: theconcentration of losartan in the pharmaceutical composition; theconcentration of an impurity in the pharmaceutical composition; thevisual appearance of the pharmaceutical composition; the viscosity ofthe pharmaceutical composition; the uniformity of the pharmaceuticalcomposition; and the sedimentation rate of the pharmaceuticalcomposition.
 153. The method of claim 147, wherein the pharmaceuticalcomposition is stable at: 15° C.-25° C. and ≤65% relative humidity, or30° C. and ≤65% relative humidity, or 40° C. and 75% relative humidity.